Lecturer: Ge Jin, Ph.D., ge.jincase, 3683791

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Cytokinesproperties, categories, signaling, function. Body as Host: Immune Molecules. Cytokines small, secreted, non-antibody proteins produced by cells involved in both innate

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Lecturer: Ge Jin, Ph.D., ge.jincase, 3683791

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2. “Cytokine” is word that comes from cyto- (cell) and –kinin (hormone). Nomenclature has been a problem because these molecules were originally named after the activity that they described, or cell types they derived from. This results in a large number of 3 or 4 letter acronyms. Names such as interleukines, chemokines, monokines, interferons, colony-growth factors are the general terms to describe cytokines fallen into different categories. Cytokines are small secreted proteins that mediate and regulate immunity, inflammation, and hematopoiesis. However, it has been shown that membrane bound forms of cytokines, such as membrane bound TNFalpha (mTNF), also exhibit biological activities. Cytokines are produced de novo in response to an immune stimulus. They generally (although not always) act over short distances and short time spans and at very low concentration. They act by binding to specific cell surface receptors, which then signal the cell via kinase cascades, often tyrosine kinases, to modulate gene expression. The gene products (proteins) participate in the cell proliferation, differentiation, migration, and apoptosis activities. “Cytokine” is word that comes from cyto- (cell) and –kinin (hormone). Nomenclature has been a problem because these molecules were originally named after the activity that they described, or cell types they derived from. This results in a large number of 3 or 4 letter acronyms. Names such as interleukines, chemokines, monokines, interferons, colony-growth factors are the general terms to describe cytokines fallen into different categories. Cytokines are small secreted proteins that mediate and regulate immunity, inflammation, and hematopoiesis. However, it has been shown that membrane bound forms of cytokines, such as membrane bound TNFalpha (mTNF), also exhibit biological activities. Cytokines are produced de novo in response to an immune stimulus. They generally (although not always) act over short distances and short time spans and at very low concentration. They act by binding to specific cell surface receptors, which then signal the cell via kinase cascades, often tyrosine kinases, to modulate gene expression. The gene products (proteins) participate in the cell proliferation, differentiation, migration, and apoptosis activities.

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6. Cytokines may act on the cells that secrete them (autocrine action), on nearby cells (paracrine action), or in some instances on distant cells (endocrine action). Cytokines may act on the cells that secrete them (autocrine action), on nearby cells (paracrine action), or in some instances on distant cells (endocrine action).

7. Cytokines can be produced by many cells types and act on many cell types (pleiotrophic). Different cytokines usually exhibit similar biological functions, a property termed redundancy. Redundancy has been considered an important feature for cytokines in that the immune response to an antigen(s) can be signaled to different effector cell types promptly. It is common for different cell types to produce the same cytokines or for a single cytokine to act on several different cell types (pleiotropy). Therefore if you have a deficiency in 1 type of cytokine, it may not be “detrimental” as you will have other cytokines to “cover” for this “problem.” However, if you have deficiency in a “shared” component (common receptor/component) used amongst many different cytokines (E.g. IL-2R?), it WILL be detrimental (i.e. may result in Severe Combined Iummno Deficiency SCID) Cytokines can be produced by many cells types and act on many cell types (pleiotrophic). Different cytokines usually exhibit similar biological functions, a property termed redundancy. Redundancy has been considered an important feature for cytokines in that the immune response to an antigen(s) can be signaled to different effector cell types promptly. It is common for different cell types to produce the same cytokines or for a single cytokine to act on several different cell types (pleiotropy). Therefore if you have a deficiency in 1 type of cytokine, it may not be “detrimental” as you will have other cytokines to “cover” for this “problem.” However, if you have deficiency in a “shared” component (common receptor/component) used amongst many different cytokines (E.g. IL-2R?), it WILL be detrimental (i.e. may result in Severe Combined Iummno Deficiency SCID)

8. An example of redundancy.An example of redundancy.

9. Cytokines are usually produced in a cascade, as one cytokine can stimulate its target cells to produce additional cytokines. Two or three cytokines can act together to show enhanced activity (synergistic), or one cytokine can attenuate the activity of the others (antagonistic). Cytokines are usually produced in a cascade, as one cytokine can stimulate its target cells to produce additional cytokines. Two or three cytokines can act together to show enhanced activity (synergistic), or one cytokine can attenuate the activity of the others (antagonistic).

10. All cytokine receptors contain a transmembrane domain (chemokine receptors have a 7 transmembrane domain) that divide the receptors into extracellular domain (for cytokine binding) and intracellular domain (for signaling). The amino-termini are located in the extracellular domain. There is a large family of cytokine receptors, which are divided into two subsets on the basis of the presence or absence of particular sequence motifs. Many cytokine receptors are members of the hematopoietin-receptor family, also called the class I cytokine receptor family. This family is named after the first of its members to be defined, the hematopoietin receptor. A smaller number of receptors fall into the class II cytokine receptor superfamily; many of these are receptors for interferons or interferon-like cytokines. Other super-families of cytokine receptors are the tumor necrosis factor-receptor (TNFR) family, and the chemokine-receptor family, which are part of a very large family of large G protein-coupled receptors. Each family member is a variant with a distinct specificity, performing a particular function on the cell that expresses it. In the hemato-poietin-receptor family, the a chain often defines the ligand specificity of the receptor, whereas the ß or ? chain confers the intracellular signaling function. For the TNFR family, the ligands act as trimers and may be associated with the cell membrane rather than being secreted. The intracellular part of the IL-1/Toll-like receptor does not contain a kinase domain, therefore the receptor does not show any kinase activity. Binding of ligand (IL-1) to its cognate receptor induces conformational changes of the intracellular domain, which induces recruitment of several cytoplasmic adaptor proteins to the receptor to form adaptor complexes. Proteins involved in the complexes will undergo modifications, such as phosphorylation and ubiquitination, resulting in the activation of the kinases that directly modulate (phosphorylate) cytoplasmic resident transcription factors. Upon modification, these transcription factors translocate into the nucleus, where they bind to their cognate DNA binding sites in the regulatory region of the target gene, in the present of other essential transcription factors, to promoter gene expression.All cytokine receptors contain a transmembrane domain (chemokine receptors have a 7 transmembrane domain) that divide the receptors into extracellular domain (for cytokine binding) and intracellular domain (for signaling). The amino-termini are located in the extracellular domain. There is a large family of cytokine receptors, which are divided into two subsets on the basis of the presence or absence of particular sequence motifs. Many cytokine receptors are members of the hematopoietin-receptor family, also called the class I cytokine receptor family. This family is named after the first of its members to be defined, the hematopoietin receptor. A smaller number of receptors fall into the class II cytokine receptor superfamily; many of these are receptors for interferons or interferon-like cytokines. Other super-families of cytokine receptors are the tumor necrosis factor-receptor (TNFR) family, and the chemokine-receptor family, which are part of a very large family of large G protein-coupled receptors. Each family member is a variant with a distinct specificity, performing a particular function on the cell that expresses it. In the hemato-poietin-receptor family, the a chain often defines the ligand specificity of the receptor, whereas the ß or ? chain confers the intracellular signaling function. For the TNFR family, the ligands act as trimers and may be associated with the cell membrane rather than being secreted. The intracellular part of the IL-1/Toll-like receptor does not contain a kinase domain, therefore the receptor does not show any kinase activity. Binding of ligand (IL-1) to its cognate receptor induces conformational changes of the intracellular domain, which induces recruitment of several cytoplasmic adaptor proteins to the receptor to form adaptor complexes. Proteins involved in the complexes will undergo modifications, such as phosphorylation and ubiquitination, resulting in the activation of the kinases that directly modulate (phosphorylate) cytoplasmic resident transcription factors. Upon modification, these transcription factors translocate into the nucleus, where they bind to their cognate DNA binding sites in the regulatory region of the target gene, in the present of other essential transcription factors, to promoter gene expression.

11. TNFR family receptors stimulates activation of the NFkB transcription factor family. Activation of TNFR regulates the expression of genes that can be induced by IL-1R/Toll-like receptor (IL-1, LPS, dsRNA….).TNFR family receptors stimulates activation of the NFkB transcription factor family. Activation of TNFR regulates the expression of genes that can be induced by IL-1R/Toll-like receptor (IL-1, LPS, dsRNA….).

12. Members of the hematopoietin family participate in stimulating growth and maturation of red blood cells, lymphocytes, and bone marrow. IL-3: recombinant human IL-3 has been produced to stimulate bone marrow function following chemotherapy. CNTF (ciliary neurotrophic factor): stimulate gene expression, cell survival or differentiation in a variety of neuronal cell types. LIF (leukemia inhibitory factor): A pleiotropic cytokine with roles in several different systems. It is involved in the induction of hemotopoietic differentiation in normal and myeloid leukemia cells, induction of neuronal cell differentiation, regulator of mesenchymal to epithelial conversion during kidney development, and may also have a role in immune tolerance at the maternal-fetal interface. OSM (oncostatin M): a growth regulator which inhibits the proliferation of a number of tumor cell lines. It regulates cytokine production, including IL-6, G-CSF and GM-CSF from endothelial cells. IL-2: The protein encoded by this gene is a secreted cytokine that is important for the proliferation of T and B lymphocytes. The receptor of this cytokine is a heterotrimeric protein complex whose gamma chain is also shared by interleukin 4 (IL4) and interleukin 7 (IL7). The expression of this gene in mature thymocytes is monoallelic, which represents an unusual regulatory mode for controlling the precise expression of a single gene. The targeted disruption of a similar gene in mice leads to ulcerative colitis-like disease, which suggests an essential role of this gene in the immune response to antigenic stimuli. IL-15: The protein encoded by this gene is a cytokine that regulates T and natural killer cell activation and proliferation. This cytokine and interleukine 2 share many biological activities. They are found to bind common hematopoietin receptor subunits, and may compete for the same receptor, and thus negatively regulate each other's activity. The number of CD8+ memory cells is shown to be controlled by a balance between this cytokine and IL2. This cytokine induces the activation of JAK kinases, as well as the phosphorylation and activation of transcription activators STAT3, STAT5, and STAT6. Studies of the mouse counterpart suggested that this cytokine may increase the expression of apoptosis inhibitor BCL2L1/BCL-x(L), possibly through the transcription activation activity of STAT6, and thus prevent apoptosis. Two alternatively spliced transcript variants of this gene encoding the same protein have been reported. IL-7: The protein encoded by this gene is a cytokine important for B and T cell development. This cytokine and the hepatocyte growth factor (HGF) form a heterodimer that functions as a pre-pro-B cell growth-stimulating factor. This cytokine is found to be a cofactor for V(D)J rearrangement of the T cell receptor beta (TCRB) during early T cell development. This cytokine can be produced locally by intestinal epithelial and epithelial goblet cells, and may serve as a regulatory factor for intestinal mucosal lymphocytes. Knockout studies in mice suggested that this cytokine plays an essential role in lymphoid cell survival. [provided by RefSeq] IL-9: The protein encoded by this gene is a cytokine that acts as a regulator of a variety of hematopoietic cells. This cytokine stimulates cell proliferation and prevents apoptosis. It functions through the interleukin 9 receptor (IL9R), which activates different signal transducer and activator (STAT) proteins and thus connects this cytokine to various biological processes. The gene encoding this cytokine has been identified as a candidate gene for asthma. Genetic studies on a mouse model of asthma demonstrated that this cytokine is a determining factor in the pathogenesis of bronchial hyperresponsiveness. [provided by RefSeq] IL6: an immunoregulatory cytokine that activates a cell surface signaling assembly composed of IL6, IL6RA (IL6R; MIM 147880), and the shared signaling receptor gp130 (IL6ST; MIM 600694). IL-6 expressed in pancreatic cancer is a factor that induces the haptoglobin production; IL6 induced the expression of fucosylation-related genes. CSF: a cytokine that controls the production, differentiation, and function of granulocytes and macrophages. The active form of the protein is found extracellularly as a homodimer. This gene has been localized to a cluster of related genes at chromosome region 5q31, which is known to be associated with interstitial deletions in the 5q- syndrome and acute myelogenous leukemia. Other genes in the cluster include those encoding interleukins 4, 5, and 13. Members of the hematopoietin family participate in stimulating growth and maturation of red blood cells, lymphocytes, and bone marrow. IL-3: recombinant human IL-3 has been produced to stimulate bone marrow function following chemotherapy. CNTF (ciliary neurotrophic factor): stimulate gene expression, cell survival or differentiation in a variety of neuronal cell types. LIF (leukemia inhibitory factor): A pleiotropic cytokine with roles in several different systems. It is involved in the induction of hemotopoietic differentiation in normal and myeloid leukemia cells, induction of neuronal cell differentiation, regulator of mesenchymal to epithelial conversion during kidney development, and may also have a role in immune tolerance at the maternal-fetal interface. OSM (oncostatin M): a growth regulator which inhibits the proliferation of a number of tumor cell lines. It regulates cytokine production, including IL-6, G-CSF and GM-CSF from endothelial cells. IL-2: The protein encoded by this gene is a secreted cytokine that is important for the proliferation of T and B lymphocytes. The receptor of this cytokine is a heterotrimeric protein complex whose gamma chain is also shared by interleukin 4 (IL4) and interleukin 7 (IL7). The expression of this gene in mature thymocytes is monoallelic, which represents an unusual regulatory mode for controlling the precise expression of a single gene. The targeted disruption of a similar gene in mice leads to ulcerative colitis-like disease, which suggests an essential role of this gene in the immune response to antigenic stimuli. IL-15: The protein encoded by this gene is a cytokine that regulates T and natural killer cell activation and proliferation. This cytokine and interleukine 2 share many biological activities. They are found to bind common hematopoietin receptor subunits, and may compete for the same receptor, and thus negatively regulate each other's activity. The number of CD8+ memory cells is shown to be controlled by a balance between this cytokine and IL2. This cytokine induces the activation of JAK kinases, as well as the phosphorylation and activation of transcription activators STAT3, STAT5, and STAT6. Studies of the mouse counterpart suggested that this cytokine may increase the expression of apoptosis inhibitor BCL2L1/BCL-x(L), possibly through the transcription activation activity of STAT6, and thus prevent apoptosis. Two alternatively spliced transcript variants of this gene encoding the same protein have been reported. IL-7: The protein encoded by this gene is a cytokine important for B and T cell development. This cytokine and the hepatocyte growth factor (HGF) form a heterodimer that functions as a pre-pro-B cell growth-stimulating factor. This cytokine is found to be a cofactor for V(D)J rearrangement of the T cell receptor beta (TCRB) during early T cell development. This cytokine can be produced locally by intestinal epithelial and epithelial goblet cells, and may serve as a regulatory factor for intestinal mucosal lymphocytes. Knockout studies in mice suggested that this cytokine plays an essential role in lymphoid cell survival. [provided by RefSeq] IL-9: The protein encoded by this gene is a cytokine that acts as a regulator of a variety of hematopoietic cells. This cytokine stimulates cell proliferation and prevents apoptosis. It functions through the interleukin 9 receptor (IL9R), which activates different signal transducer and activator (STAT) proteins and thus connects this cytokine to various biological processes. The gene encoding this cytokine has been identified as a candidate gene for asthma. Genetic studies on a mouse model of asthma demonstrated that this cytokine is a determining factor in the pathogenesis of bronchial hyperresponsiveness. [provided by RefSeq] IL6: an immunoregulatory cytokine that activates a cell surface signaling assembly composed of IL6, IL6RA (IL6R; MIM 147880), and the shared signaling receptor gp130 (IL6ST; MIM 600694). IL-6 expressed in pancreatic cancer is a factor that induces the haptoglobin production; IL6 induced the expression of fucosylation-related genes. CSF: a cytokine that controls the production, differentiation, and function of granulocytes and macrophages. The active form of the protein is found extracellularly as a homodimer. This gene has been localized to a cluster of related genes at chromosome region 5q31, which is known to be associated with interstitial deletions in the 5q- syndrome and acute myelogenous leukemia. Other genes in the cluster include those encoding interleukins 4, 5, and 13.

14. The chemokines are a large family of small proteins represented here by IL-8 (upper molecule). Each chemokine is thought to have a similar structure. The receptors for the chemokines are members of the large family of seven-span receptors, which also includes the photoreceptor protein rhodopsin and many other receptors. They have seven trans-membrane helices, and all members of this receptor family interact with G proteins. The only solved structure of a seven-span membrane protein is of the bacterial protein bacteriorhodopsin; it is depicted in the right structure, showing the orientation of the seven trans-membrane helices (blue) with the bound ligand (in this case retinal) in red. Essentially all of this structure would be embedded within the cell membrane. Cylinders represent a helices and arrows ß strands. The chemokines are a large family of small proteins represented here by IL-8 (upper molecule). Each chemokine is thought to have a similar structure. The receptors for the chemokines are members of the large family of seven-span receptors, which also includes the photoreceptor protein rhodopsin and many other receptors. They have seven trans-membrane helices, and all members of this receptor family interact with G proteins. The only solved structure of a seven-span membrane protein is of the bacterial protein bacteriorhodopsin; it is depicted in the right structure, showing the orientation of the seven trans-membrane helices (blue) with the bound ligand (in this case retinal) in red. Essentially all of this structure would be embedded within the cell membrane. Cylinders represent a helices and arrows ß strands.

15. The family of TGF-beta receptor consists of two receptor types. TGF-beta receptors are serine-threnine kinases. Type II TGF-beta receptor (TbRII) is constitutively phosphorylated and has high affinity for ligand binding. However, the intracellular domain of TbRII cannot signal to downstream effector molecules. Type I TGF-beta receptor (TbRI) is unphosphorylated in resting cells and has lower affinity for TGF-beta binding. Binding of ligand to the constitutively active type II TGFb receptor (TbRII) promotes complex formation with the type I receptor (TbRI). Subsequent phosphorylation and activation of TbRI by TbRII leads to further propagation of TGF-beta signaling by several signaling cascades, including the Smads, MAPK, PKC, and PI-3K/AKT. In most cells, receptor-regulated Smads (R-Smads), Smad2 and Smad3, are directly phosphorylated and activated by TbRI, which leads to the formation of multimeric complexes with the common-mediator Smad, or co-Smad, Smad4. The Smad complexes translocate to the nucleus, where they regulate gene expression by directly interacting with DNA-binding proteins and by recruiting co-activators or co-repressors of the promoter. The family of TGF-beta receptor consists of two receptor types. TGF-beta receptors are serine-threnine kinases. Type II TGF-beta receptor (TbRII) is constitutively phosphorylated and has high affinity for ligand binding. However, the intracellular domain of TbRII cannot signal to downstream effector molecules. Type I TGF-beta receptor (TbRI) is unphosphorylated in resting cells and has lower affinity for TGF-beta binding. Binding of ligand to the constitutively active type II TGFb receptor (TbRII) promotes complex formation with the type I receptor (TbRI). Subsequent phosphorylation and activation of TbRI by TbRII leads to further propagation of TGF-beta signaling by several signaling cascades, including the Smads, MAPK, PKC, and PI-3K/AKT. In most cells, receptor-regulated Smads (R-Smads), Smad2 and Smad3, are directly phosphorylated and activated by TbRI, which leads to the formation of multimeric complexes with the common-mediator Smad, or co-Smad, Smad4. The Smad complexes translocate to the nucleus, where they regulate gene expression by directly interacting with DNA-binding proteins and by recruiting co-activators or co-repressors of the promoter.

19. Stimulation of IL-1 receptor leads to the activation of the transcription factor NF?B. In unstimulated cells NF?B-family proteins exist as hetero- or homodimers that are sequestered in the cytoplasm by virtue of their association with a member of the I?B family of inhibitory proteins. Extracellular signals (IL-1) can lead to the activation of I?B kinase (IKK), which in turn phosphorylates two specific serine residuals on I?B proteins (S32 and S36). Phospho-I?B is then recognized by ubiquitin ligase complex, leading to its ubiquitination and degradation by the proteasome. The destruction of I?B unmasks the nuclear localization signal of NF?B, leading to its nuclear translocation and binding to the promoters of target genes. Activation of the IKK complex involves the phosphorylation of two serine residues located in the activation loop within the kinase domain. The IKKa and IKKß subunits preferentially form heterodimers, and both can directly phosphorylate the critical S32 and S36 residues of I?Ba.Stimulation of IL-1 receptor leads to the activation of the transcription factor NF?B. In unstimulated cells NF?B-family proteins exist as hetero- or homodimers that are sequestered in the cytoplasm by virtue of their association with a member of the I?B family of inhibitory proteins. Extracellular signals (IL-1) can lead to the activation of I?B kinase (IKK), which in turn phosphorylates two specific serine residuals on I?B proteins (S32 and S36). Phospho-I?B is then recognized by ubiquitin ligase complex, leading to its ubiquitination and degradation by the proteasome. The destruction of I?B unmasks the nuclear localization signal of NF?B, leading to its nuclear translocation and binding to the promoters of target genes. Activation of the IKK complex involves the phosphorylation of two serine residues located in the activation loop within the kinase domain. The IKKa and IKKß subunits preferentially form heterodimers, and both can directly phosphorylate the critical S32 and S36 residues of I?Ba.

20. LT-B: lymphotoxin-beta (Xenopus) BAFF: B-cell activating factor (mouse)LT-B: lymphotoxin-beta (Xenopus) BAFF: B-cell activating factor (mouse)

22. Cytokine binding results in the dimerization/oligomerization of receptors, which leads to the juxtapositioning of JAKs. The recruitment of JAKs induces their phosphorylation, apparently via autophosphorylation or cross-phosphorylation by other JAKs, or by other families of kinases. Activated JAKs then phosphorylates receptors on target tyrosine sites. The phosphorylated receptor sites can serve as docking sites that allow binding of STATs and other SH2-domain containing signal molecules, such as Src-kinases, Shc, Grb2, and PI3K. Upon binding to the receptor, all members of the STAT family become tyrosine phosphorylated in response to cytokine stimulation at a conserved C-terminal tyrosine. Phosphorylation of the site appears to be achieved by activated by receptors of growth factors as well as by JAK and Src-kinases. Once phosphrylated, STATs form homo- or hetero-dimers via the interaction of the SH2 domain of one STAT molecule with the phosphorylated residue of the another. The dimerzied STATs are able to translocate into the nucleus, where they bind to the STAT binding site of the target gene to modulate its expression. Several molecules that can be up-regulated by JAK-STAT signaling play the role in down-regulation of the pathway. The suppressor of cytokine signaling (SOCS) protein family and several other proteins contain SH2 domains. These proteins are expressed at low levels and can be induced by cytokine signaling, such as IFNg stimulation. The SH2 domain of SOCS binds directly to tyrosine phophorylated JAKs, resulting in the direct inhibition of JAK activity. The negative-feedback mechanism provides cells with addition regulation that might be crucial for immunity regulation.Cytokine binding results in the dimerization/oligomerization of receptors, which leads to the juxtapositioning of JAKs. The recruitment of JAKs induces their phosphorylation, apparently via autophosphorylation or cross-phosphorylation by other JAKs, or by other families of kinases. Activated JAKs then phosphorylates receptors on target tyrosine sites. The phosphorylated receptor sites can serve as docking sites that allow binding of STATs and other SH2-domain containing signal molecules, such as Src-kinases, Shc, Grb2, and PI3K. Upon binding to the receptor, all members of the STAT family become tyrosine phosphorylated in response to cytokine stimulation at a conserved C-terminal tyrosine. Phosphorylation of the site appears to be achieved by activated by receptors of growth factors as well as by JAK and Src-kinases. Once phosphrylated, STATs form homo- or hetero-dimers via the interaction of the SH2 domain of one STAT molecule with the phosphorylated residue of the another. The dimerzied STATs are able to translocate into the nucleus, where they bind to the STAT binding site of the target gene to modulate its expression. Several molecules that can be up-regulated by JAK-STAT signaling play the role in down-regulation of the pathway. The suppressor of cytokine signaling (SOCS) protein family and several other proteins contain SH2 domains. These proteins are expressed at low levels and can be induced by cytokine signaling, such as IFNg stimulation. The SH2 domain of SOCS binds directly to tyrosine phophorylated JAKs, resulting in the direct inhibition of JAK activity. The negative-feedback mechanism provides cells with addition regulation that might be crucial for immunity regulation.

24. CC chemokines: also called beta-chemokines, have two adjacent cysteines near their amino terminus. There are about 27 distinct members of this subgroup for mammals, called CC chemokine ligands (CCL1-28). Chemokines of this subfamily usually contain four cysteines (C4-CC chemokines), but a small number of CC chemokines possess six cysteines (C6-CC chemokines). C6-CC chemokines include CCL1, CCL15, CCL21, CCL23 and CCL28.[2] CC chemokines induce the migration of monocytes and other cell types such as NK cells and dendritic cells. An example of a CC chemokine is monocyte chemoattractant protein-1 (MCP-1 or CCL2) which induces monocytes to leave the bloodstream and enter the surrounding tissue to become tissue macrophages. CC chemokines induce cellular migration by binding to and activating CC chemokine receptors, ten of which have been discovered to date and called CCR1-10. These receptors are expressed on the surface of different cell types allowing their specific attraction by the chemokines. A CC chemokine that attracts lymphocytes is CCL28, which is chemoattractant to T cells and B cells that express the chemokine receptor CCR10. This chemokine can also attract eosinophils that express CCR3. CCL5 (or RANTES) attracts cells such as T cells, eosinophils and basophils that express the receptor CCR5. CXC chemokines: The two N-terminal cysteines of CXC chemokines (or a-chemokines) are separated by one amino acid, represented in this name with an "X". There have been 17 different CXC chemokines described in mammals, that are subdivided into two categories, those with a specific amino acid sequence (or motif) of glutamic acid-leucine-arginine (or ELR for short) immediately before the first cysteine of the CXC motif (ELR-positive), and those without an ELR motif (ELR-negative). ELR-positive CXC chemokines specifically induce the migration of neutrophils, and interact with chemokine receptors CXCR1 and CXCR2. An example of an ELR-positive CXC chemokine is interleukin-8 (IL-8), which induces neutrophils to leave the bloodstream and enter into the surrounding tissue. Other CXC chemokines that lack the ELR motif, such as CXCL13, tend to be chemoattractant for lymphocytes. CXC chemokines bind to CXC chemokine receptors, of which seven have been discovered to date, designated CXCR1-7. Other chemokine subgroups include C chemokines and CX3C chemokines. Chemokine receptors: Chemokine receptors are G protein-coupled receptors containing 7 transmembrane domains that are found on the surface of leukocytes. Approximately 19 different chemokine receptors have been characterized to date, which are divided into four families depending on the type of chemokine they bind; CXCR that bind CXC chemokines, CCR that bind CC chemokines, CX3CR1 that binds the sole CX3C chemokine (CX3CL1), and XCR1 that binds the two XC chemokines (XCL1 and XCL2). They share many structural features; they are similar in size (with about 350 amino acids), have a short, acidic N-terminal end, seven helical transmembrane domains with three intracellular and three extracellular hydrophilic loops, and an intracellular C-terminus containing serine and threonine residues important for receptor regulation. The first two extracellular loops of chemokine receptors each has a conserved cysteine residue that allow formation of a disulfide bridge between these loops. G proteins are coupled to the C-terminal end of the chemokine receptor to allow intracellular signaling after receptor activation, while the N-terminal domain of the chemokine receptor determines ligand binding specificity. CC chemokines: also called beta-chemokines, have two adjacent cysteines near their amino terminus. There are about 27 distinct members of this subgroup for mammals, called CC chemokine ligands (CCL1-28). Chemokines of this subfamily usually contain four cysteines (C4-CC chemokines), but a small number of CC chemokines possess six cysteines (C6-CC chemokines). C6-CC chemokines include CCL1, CCL15, CCL21, CCL23 and CCL28.[2] CC chemokines induce the migration of monocytes and other cell types such as NK cells and dendritic cells. An example of a CC chemokine is monocyte chemoattractant protein-1 (MCP-1 or CCL2) which induces monocytes to leave the bloodstream and enter the surrounding tissue to become tissue macrophages. CC chemokines induce cellular migration by binding to and activating CC chemokine receptors, ten of which have been discovered to date and called CCR1-10. These receptors are expressed on the surface of different cell types allowing their specific attraction by the chemokines. A CC chemokine that attracts lymphocytes is CCL28, which is chemoattractant to T cells and B cells that express the chemokine receptor CCR10. This chemokine can also attract eosinophils that express CCR3. CCL5 (or RANTES) attracts cells such as T cells, eosinophils and basophils that express the receptor CCR5. CXC chemokines: The two N-terminal cysteines of CXC chemokines (or a-chemokines) are separated by one amino acid, represented in this name with an "X". There have been 17 different CXC chemokines described in mammals, that are subdivided into two categories, those with a specific amino acid sequence (or motif) of glutamic acid-leucine-arginine (or ELR for short) immediately before the first cysteine of the CXC motif (ELR-positive), and those without an ELR motif (ELR-negative). ELR-positive CXC chemokines specifically induce the migration of neutrophils, and interact with chemokine receptors CXCR1 and CXCR2. An example of an ELR-positive CXC chemokine is interleukin-8 (IL-8), which induces neutrophils to leave the bloodstream and enter into the surrounding tissue. Other CXC chemokines that lack the ELR motif, such as CXCL13, tend to be chemoattractant for lymphocytes. CXC chemokines bind to CXC chemokine receptors, of which seven have been discovered to date, designated CXCR1-7. Other chemokine subgroups include C chemokines and CX3C chemokines. Chemokine receptors: Chemokine receptors are G protein-coupled receptors containing 7 transmembrane domains that are found on the surface of leukocytes. Approximately 19 different chemokine receptors have been characterized to date, which are divided into four families depending on the type of chemokine they bind; CXCR that bind CXC chemokines, CCR that bind CC chemokines, CX3CR1 that binds the sole CX3C chemokine (CX3CL1), and XCR1 that binds the two XC chemokines (XCL1 and XCL2). They share many structural features; they are similar in size (with about 350 amino acids), have a short, acidic N-terminal end, seven helical transmembrane domains with three intracellular and three extracellular hydrophilic loops, and an intracellular C-terminus containing serine and threonine residues important for receptor regulation. The first two extracellular loops of chemokine receptors each has a conserved cysteine residue that allow formation of a disulfide bridge between these loops. G proteins are coupled to the C-terminal end of the chemokine receptor to allow intracellular signaling after receptor activation, while the N-terminal domain of the chemokine receptor determines ligand binding specificity.

25. Signal transduction of chemokine receptors (general): Chemokine receptors associate with G-proteins to transmit cell signals following ligand binding. Activation of G proteins, by chemokine receptors, causes the subsequent activation of an enzyme known as phospholipase C (PLC). PLC cleaves a molecule called phosphatidylinositol (4,5)-bisphosphate (PIP2) into two second messenger molecules known as Inositol triphosphate (IP3) and diacylglycerol (DAG) that trigger intracellular signaling events; DAG activates another enzyme called protein kinase C (PKC), and IP3 triggers the release of calcium from intracellular stores. These events promote many signaling cascades (such as the MAP kinase pathway) that generate responses like chemotaxis, degranulation, release of superoxide anions and changes in the avidity of cell adhesion molecules called integrins within the cell harbouring the chemokine receptor. SDF (stromal derived factor, also called CXCL12) is a chemokine that play roles in chemotaxis and HIV entry into cells. SDF binding to the cognate receptor CXCR4 leads to the activation of multiple G protein-dependent signaling pathways. Activation of the G-alpha i protein results in the disassociation of their hetertrimers into alpha, beta, and gamma subunits, therefore activate downstream effectors including PI-3K, MAPK, and PLC. The following signaling cascades lead to a verities of functional outcomes, such as chemotaxis, polarization, and adhesion. Desensitization of the receptor starts from phosphorylation of the C-terminal receptor tail, which increases the affinity of beta-arrestin proteins for the receptor and prevents further interaction between chemokine receptors and the G protein. The formation of GRK-beta-arrestin complex, together with the receptor, prompt the clatherin-mediated internalization of the ligand-receptor complex and entry into vesicles. The internalization and vesiclization require GTPase activity of dynamin (not shown in the slide). The coupled ligand (SDF) will be degraded and the receptor is either recycled or degradaded. Signal transduction of chemokine receptors (general): Chemokine receptors associate with G-proteins to transmit cell signals following ligand binding. Activation of G proteins, by chemokine receptors, causes the subsequent activation of an enzyme known as phospholipase C (PLC). PLC cleaves a molecule called phosphatidylinositol (4,5)-bisphosphate (PIP2) into two second messenger molecules known as Inositol triphosphate (IP3) and diacylglycerol (DAG) that trigger intracellular signaling events; DAG activates another enzyme called protein kinase C (PKC), and IP3 triggers the release of calcium from intracellular stores. These events promote many signaling cascades (such as the MAP kinase pathway) that generate responses like chemotaxis, degranulation, release of superoxide anions and changes in the avidity of cell adhesion molecules called integrins within the cell harbouring the chemokine receptor. SDF (stromal derived factor, also called CXCL12) is a chemokine that play roles in chemotaxis and HIV entry into cells. SDF binding to the cognate receptor CXCR4 leads to the activation of multiple G protein-dependent signaling pathways. Activation of the G-alpha i protein results in the disassociation of their hetertrimers into alpha, beta, and gamma subunits, therefore activate downstream effectors including PI-3K, MAPK, and PLC. The following signaling cascades lead to a verities of functional outcomes, such as chemotaxis, polarization, and adhesion. Desensitization of the receptor starts from phosphorylation of the C-terminal receptor tail, which increases the affinity of beta-arrestin proteins for the receptor and prevents further interaction between chemokine receptors and the G protein. The formation of GRK-beta-arrestin complex, together with the receptor, prompt the clatherin-mediated internalization of the ligand-receptor complex and entry into vesicles. The internalization and vesiclization require GTPase activity of dynamin (not shown in the slide). The coupled ligand (SDF) will be degraded and the receptor is either recycled or degradaded.

29. TNF-alpha is produced primarily by macrophages in response to gram-negative bacterial LPS. It recruits macrophages and neutralphils and stimulates endothelial cells to produce intercellular adhesion molecule ICAM for migration of these cells move into tissue and get to the site of infection. It also stimulates endothelial cells to produce chemokines, chemotactic cytokines that are able to chemoattract macrophages and PMNs. TNF alpha is a pyrogen that act on hyperthymus to produce fever. It also acts on liver to produce acute phase protein. Lots of the inflammation effects are due to TNF. It also inhibits production of TGF-beta, an important cytokine involved in immune suppression. TNF was originally identified in mouse serum after injection with Mycobacterium bovis strain bacillus Calmette-Guerin (BCG) and endotoxin. Serum from such animals was cytotoxic or cytostatic to a number of mouse and human transformed cell lines and produced hemorrhagic necrosis and in some instances complete regression of certain transplanted tumors in mice. (OMIM) Tumor necrosis factor-alpha (cachectin), potent proinflammatory cytokine, involved in inflammatory and immune responses, stimulating the sphingomyelinase (SMPD1), enhancing insulin resistance in peripheral tissues of cancer patients, susceptibility factor for narcolepsy and myasthenia gravis and cardiac sarcoidosis, with a common polymorphism in the promoter region (C->A) associated with reduced circulating levels of TNF, mediating neuronal death in injured brain (by inducing resistance to the protective effect of IGF1). (GeneCard) TNF binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. TNF-alpha is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation. TNF-alpha is produced primarily by macrophages in response to gram-negative bacterial LPS. It recruits macrophages and neutralphils and stimulates endothelial cells to produce intercellular adhesion molecule ICAM for migration of these cells move into tissue and get to the site of infection. It also stimulates endothelial cells to produce chemokines, chemotactic cytokines that are able to chemoattract macrophages and PMNs. TNF alpha is a pyrogen that act on hyperthymus to produce fever. It also acts on liver to produce acute phase protein. Lots of the inflammation effects are due to TNF. It also inhibits production of TGF-beta, an important cytokine involved in immune suppression. TNF was originally identified in mouse serum after injection with Mycobacterium bovis strain bacillus Calmette-Guerin (BCG) and endotoxin. Serum from such animals was cytotoxic or cytostatic to a number of mouse and human transformed cell lines and produced hemorrhagic necrosis and in some instances complete regression of certain transplanted tumors in mice. (OMIM) Tumor necrosis factor-alpha (cachectin), potent proinflammatory cytokine, involved in inflammatory and immune responses, stimulating the sphingomyelinase (SMPD1), enhancing insulin resistance in peripheral tissues of cancer patients, susceptibility factor for narcolepsy and myasthenia gravis and cardiac sarcoidosis, with a common polymorphism in the promoter region (C->A) associated with reduced circulating levels of TNF, mediating neuronal death in injured brain (by inducing resistance to the protective effect of IGF1). (GeneCard) TNF binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. TNF-alpha is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation.

30. TNFa is the most important cytokine involved in a variety of immune responses. TNFa has several functions in inflammation. It is prothrombotic and promotes leukocyte adhesion and migration (top). It has an important role in the regulation of macrophage activation and immune responses in tissues (center), and it also modulates hematopoiesis and lymphocyte development (bottom). (Male, David. Immunology, 7th Edition. C.V. Mosby, 04/24/2006.).TNFa is the most important cytokine involved in a variety of immune responses. TNFa has several functions in inflammation. It is prothrombotic and promotes leukocyte adhesion and migration (top). It has an important role in the regulation of macrophage activation and immune responses in tissues (center), and it also modulates hematopoiesis and lymphocyte development (bottom). (Male, David. Immunology, 7th Edition. C.V. Mosby, 04/24/2006.).

31. IL-1 is produced by macrophages. Its properties are very similar to TNF. It is also a pyrogen. It does lots of things TNF does. It also activate T cells when microphages present antigen to T cells, macrophage produced IL-1 is able to activate T cells. It is one of the cytokines that are involved in T cell activation. Both TNF and IL-1 are key cytokines in the process of chronic joint inflammation and the concomitant erosive changes in cartilage and bone. IL-1 is the secondary mediator responsible for the arthritic changes, and TNF-alpha alone is neither arthritogenic nor destructive towards joints.IL-1 is produced by macrophages. Its properties are very similar to TNF. It is also a pyrogen. It does lots of things TNF does. It also activate T cells when microphages present antigen to T cells, macrophage produced IL-1 is able to activate T cells. It is one of the cytokines that are involved in T cell activation. Both TNF and IL-1 are key cytokines in the process of chronic joint inflammation and the concomitant erosive changes in cartilage and bone. IL-1 is the secondary mediator responsible for the arthritic changes, and TNF-alpha alone is neither arthritogenic nor destructive towards joints.

32. IL-10 is a modulatory cytokine involved in many inflammatory diseases. Monocytes and Th2 cells are considered sources of IL-10 production. IL-10 was isolated as human cytokine synthesis inhibitory factor (CSIF); it plays an important role on suppressing inflammatory responses. It inhibits a lot of things. It inhibits the synthesis of IFN-gamma, IL-2, IL-3, TNF-alpha, and GM-CSF by cells such as macrophages and Th1 cells. It inhibits production of IFN-gamma in Th1 cells, switching the Th1 response to dominantly Th2 response. It also inhibits production of class II MHC, a co-stimulatory protein on macrophages. As a consequence of that, APCs are not able to present antigen to T cells, therefore T cells will not be activated. This is an example of immunoregulation by inhibiting effects.IL-10 is a modulatory cytokine involved in many inflammatory diseases. Monocytes and Th2 cells are considered sources of IL-10 production. IL-10 was isolated as human cytokine synthesis inhibitory factor (CSIF); it plays an important role on suppressing inflammatory responses. It inhibits a lot of things. It inhibits the synthesis of IFN-gamma, IL-2, IL-3, TNF-alpha, and GM-CSF by cells such as macrophages and Th1 cells. It inhibits production of IFN-gamma in Th1 cells, switching the Th1 response to dominantly Th2 response. It also inhibits production of class II MHC, a co-stimulatory protein on macrophages. As a consequence of that, APCs are not able to present antigen to T cells, therefore T cells will not be activated. This is an example of immunoregulation by inhibiting effects.

33. IL-12 is produced by macrophages and dendritic cells. It stimulates production of IFN-gamma; therefore it is involved in the activation and differentiation of Th1 cells and directs Th1 cell response. It also enhances cytolytic function of T cells and NK cells.IL-12 is produced by macrophages and dendritic cells. It stimulates production of IFN-gamma; therefore it is involved in the activation and differentiation of Th1 cells and directs Th1 cell response. It also enhances cytolytic function of T cells and NK cells.

34. The pleiotropic cytokines IFN-a, originally referred to as leukocyte interferon, and IFN-ß, originally referred to as fibroblast interferon, are type I interferons that are secreted by virus-infected cells. Infection by most viruses causes a reaction in the host that includes innate and adaptive immune responses, such as the production of cytokines, increased expression of MHC class I and cytotoxic T cell mobilization. IFN-a and IFN-ß appear to be central players in innate immune responses. IFN-a and IFN-ß also have the unique ability to regulate adaptive T cell responses, perhaps directly by stimulating production of IFN-? by activated T cells or indirectly by inhibiting IL-4-inducible gene expression in monocytes. These properties have been verified in knockout mice. Mice lacking the type I IFN receptor (CD118) exhibit impaired antiviral defenses and are deficient in promoting IFN-? production by T cells. The prime role of type I interferon is to inhibit virus replication. In the immune system, it increases the production of class I MHC, which will make the cells more susceptible to cytotoxic T cell killing. It can also activate NK cells. The pleiotropic cytokines IFN-a, originally referred to as leukocyte interferon, and IFN-ß, originally referred to as fibroblast interferon, are type I interferons that are secreted by virus-infected cells. Infection by most viruses causes a reaction in the host that includes innate and adaptive immune responses, such as the production of cytokines, increased expression of MHC class I and cytotoxic T cell mobilization. IFN-a and IFN-ß appear to be central players in innate immune responses. IFN-a and IFN-ß also have the unique ability to regulate adaptive T cell responses, perhaps directly by stimulating production of IFN-? by activated T cells or indirectly by inhibiting IL-4-inducible gene expression in monocytes. These properties have been verified in knockout mice. Mice lacking the type I IFN receptor (CD118) exhibit impaired antiviral defenses and are deficient in promoting IFN-? production by T cells. The prime role of type I interferon is to inhibit virus replication. In the immune system, it increases the production of class I MHC, which will make the cells more susceptible to cytotoxic T cell killing. It can also activate NK cells.

35. IFN-gamma is primarily produced by Th1 cells, but Tc and NK cells can also produce some amount of this cytokine as well. It can induce the expression of ICAM in endothelial cells. It can activate NK cells. It also increase class I and class II MHC antigen expression, which make cells more cytotoxic and help Th cells and APC interaction, make them better antibody presenting cells. It can also activate NK cells. It can affect endothelial cells. It can also stop block division of B cells and promote their differentiation into plasma cells. IFN-gamma and IL-12 are able to induce the differentiation of pre-cytotoxic T cells into Tc cells. It also has some antiviral activity, but much weaker compared to type I interferons. IFN-?, also known as immune interferon or type II interferon, is secreted by activated T cells (Th1 cells) and NK cells. It was originally identified as an antiviral agent and its gene was mapped to human chromosome 12 and mouse chromosome 10. IFN-? signals through its own CDw119 receptor and has many biological functions. For example, IFN-? can stimulate macrophages, increase antigen processing and expression of MHC molecules, promote an Ig class switch to IgG2a antibody secretion, and control the proliferation of transformed cells. The immunomodulatory function of IFN-?, however, has become a major research focus for this cytokine. IFN-? secretion is the hallmark of proinflammatory Th1 cells but its exact role in T cell subset differentiation remains unclear. Th1 responses are associated with cell-mediated immunity and can best deal with intracellular invaders. Mice with mutations in IFN-? or IFN-? receptor expression show decreased macrophage and NK cell activity and increased susceptibility to many intracellular pathogens and viruses. Cell-mediated immune responses can still develop in IFN-? knockout mice even though enhancements in Th2-type responses can be observed. As discussed above, IL-12 plays a critical role in eliciting Th1 responses. IFN-? may act in synergy with IL-12 to accelerate development of the Th1 cell subset and also repress Th2 cells either directly or indirectly. IFN-gamma is primarily produced by Th1 cells, but Tc and NK cells can also produce some amount of this cytokine as well. It can induce the expression of ICAM in endothelial cells. It can activate NK cells. It also increase class I and class II MHC antigen expression, which make cells more cytotoxic and help Th cells and APC interaction, make them better antibody presenting cells. It can also activate NK cells. It can affect endothelial cells. It can also stop block division of B cells and promote their differentiation into plasma cells. IFN-gamma and IL-12 are able to induce the differentiation of pre-cytotoxic T cells into Tc cells. It also has some antiviral activity, but much weaker compared to type I interferons. IFN-?, also known as immune interferon or type II interferon, is secreted by activated T cells (Th1 cells) and NK cells. It was originally identified as an antiviral agent and its gene was mapped to human chromosome 12 and mouse chromosome 10. IFN-? signals through its own CDw119 receptor and has many biological functions. For example, IFN-? can stimulate macrophages, increase antigen processing and expression of MHC molecules, promote an Ig class switch to IgG2a antibody secretion, and control the proliferation of transformed cells. The immunomodulatory function of IFN-?, however, has become a major research focus for this cytokine. IFN-? secretion is the hallmark of proinflammatory Th1 cells but its exact role in T cell subset differentiation remains unclear. Th1 responses are associated with cell-mediated immunity and can best deal with intracellular invaders. Mice with mutations in IFN-? or IFN-? receptor expression show decreased macrophage and NK cell activity and increased susceptibility to many intracellular pathogens and viruses. Cell-mediated immune responses can still develop in IFN-? knockout mice even though enhancements in Th2-type responses can be observed. As discussed above, IL-12 plays a critical role in eliciting Th1 responses. IFN-? may act in synergy with IL-12 to accelerate development of the Th1 cell subset and also repress Th2 cells either directly or indirectly.

36. Chemokines are a family of low molecular weight chemotactic cytokines that regulate leukocyte migration through interactions with seven-transmembrane, rhodopsin-like G protein-coupled receptors. Chemokines have significant structural homology and overlapping functions and can often bind to more than one receptor. In general, ligand binding results in chemokine receptor activation hallmarked by the phosphorylation of carboxyl-terminal serine/threonine residues, dissociation of heterotrimeric G proteins, generation of inositol trisphosphate, intracellular calcium release and activation of protein kinase C (PKC). With additional activation of the Ras and Rho families of guanosine triphosphate (GTP)-binding proteins, chemokine receptors mediate multiple signaling pathways that regulate a wide variety of cellular responses. Our understanding of the roles of chemokines in physiological and pathological processes has advanced significantly. It has become clear that in addition to wound healing, metastasis, angiogenesis/angiostasis, cell recruitment, lymphoid organ development, and lymphoid trafficking, chemokines are fundamental in mediating innate and adaptive immune responses by their ability to activate cells of the immune system. Chemokines play a pivotal role in regulatory and inflammatory responses just like cytokines. For example, chemokines and their receptors have been associated with predominant Th1 or Th2 responses. SDF-1/CXCL12-mutated mice exhibit a normal T cell compartment but have dramatic defects in B cell lymphopoiesis and myelopoiesis at the level of the bone marrow. This result supports the critical role of SDF-1/CXCL12 as a modulator of progenitor cell development in the bone marrow. Knocking out the CXCR2 gene leads to impaired neutrophil migration in response to CXC chemokines, increases in circulating neutrophil numbers, and a dramatic increase in B cells. Chemokines are a family of low molecular weight chemotactic cytokines that regulate leukocyte migration through interactions with seven-transmembrane, rhodopsin-like G protein-coupled receptors. Chemokines have significant structural homology and overlapping functions and can often bind to more than one receptor. In general, ligand binding results in chemokine receptor activation hallmarked by the phosphorylation of carboxyl-terminal serine/threonine residues, dissociation of heterotrimeric G proteins, generation of inositol trisphosphate, intracellular calcium release and activation of protein kinase C (PKC). With additional activation of the Ras and Rho families of guanosine triphosphate (GTP)-binding proteins, chemokine receptors mediate multiple signaling pathways that regulate a wide variety of cellular responses. Our understanding of the roles of chemokines in physiological and pathological processes has advanced significantly. It has become clear that in addition to wound healing, metastasis, angiogenesis/angiostasis, cell recruitment, lymphoid organ development, and lymphoid trafficking, chemokines are fundamental in mediating innate and adaptive immune responses by their ability to activate cells of the immune system. Chemokines play a pivotal role in regulatory and inflammatory responses just like cytokines. For example, chemokines and their receptors have been associated with predominant Th1 or Th2 responses. SDF-1/CXCL12-mutated mice exhibit a normal T cell compartment but have dramatic defects in B cell lymphopoiesis and myelopoiesis at the level of the bone marrow. This result supports the critical role of SDF-1/CXCL12 as a modulator of progenitor cell development in the bone marrow. Knocking out the CXCR2 gene leads to impaired neutrophil migration in response to CXC chemokines, increases in circulating neutrophil numbers, and a dramatic increase in B cells.

38. IL-2 is primarily produced by Th1 cells, though Tc cells can produce some of the cytokine. It is a growth factor, used to be called T cell growth factor. It is also a B cells growth factor to promote proliferation of B cells. IL-2 is required for proliferation and differentiation of T cells. It is an NK activator to activate NK cells and monocytes. Professional APC presents antigen peptide to the T cell receptor, and its surface B7 ligates T cell CD28, activating the T cell to produce IL-2 and its receptor (IL-2R). The cytokine acts in an autocrine fashion. The cell divides and differentiates into an effector T cell, which no longer requires signal for its effector function. At the termination of the immune response, CTLA-4 replaces CD28 and downregulates T cell function via reducing the expression of IL-2 receptor. (modified from Male, David. Immunology, 7th Edition. C.V. Mosby, 04/24/2006.) IL-2 is expressed from a gene on human chromosome 4 or mouse chromosome 3 and is mainly secreted by activated T cells. IL-2 and the heteromultimeric IL-2 receptor (IL-2R) complex (combinations of IL-2Ra/CD25, IL-2Rß/CD122 and ?c) are upregulated on T cells following antigenic or mitogenic stimulation leading to clonal expansion. As such, IL-2 is commonly regarded as an autocrine or paracrine T cell growth factor but it actually has effects on many cell types, such as B cells, NK cells, macrophages and neutrophils. The IL-2 knockout mouse exhibits immune dysregulation caused by defects in T cell responsiveness in vitro; however, only delays in normal T cell functionality were found in vivo. Interestingly, IL-2Ra-and IL-2Rß-deficient mice exhibit loss of T cell regulation and autoimmunity, indicating that proper IL-2 signaling may be required to induce regulatory T cells and/or eliminate abnormally activated T cells via the reversal of T cell anergy or apoptosis (programmed cell death) induction, respectively.IL-2 is primarily produced by Th1 cells, though Tc cells can produce some of the cytokine. It is a growth factor, used to be called T cell growth factor. It is also a B cells growth factor to promote proliferation of B cells. IL-2 is required for proliferation and differentiation of T cells. It is an NK activator to activate NK cells and monocytes. Professional APC presents antigen peptide to the T cell receptor, and its surface B7 ligates T cell CD28, activating the T cell to produce IL-2 and its receptor (IL-2R). The cytokine acts in an autocrine fashion. The cell divides and differentiates into an effector T cell, which no longer requires signal for its effector function. At the termination of the immune response, CTLA-4 replaces CD28 and downregulates T cell function via reducing the expression of IL-2 receptor. (modified from Male, David. Immunology, 7th Edition. C.V. Mosby, 04/24/2006.) IL-2 is expressed from a gene on human chromosome 4 or mouse chromosome 3 and is mainly secreted by activated T cells. IL-2 and the heteromultimeric IL-2 receptor (IL-2R) complex (combinations of IL-2Ra/CD25, IL-2Rß/CD122 and ?c) are upregulated on T cells following antigenic or mitogenic stimulation leading to clonal expansion. As such, IL-2 is commonly regarded as an autocrine or paracrine T cell growth factor but it actually has effects on many cell types, such as B cells, NK cells, macrophages and neutrophils. The IL-2 knockout mouse exhibits immune dysregulation caused by defects in T cell responsiveness in vitro; however, only delays in normal T cell functionality were found in vivo. Interestingly, IL-2Ra-and IL-2Rß-deficient mice exhibit loss of T cell regulation and autoimmunity, indicating that proper IL-2 signaling may be required to induce regulatory T cells and/or eliminate abnormally activated T cells via the reversal of T cell anergy or apoptosis (programmed cell death) induction, respectively.

39. Is a glycoprotein of 15 to 19 kD. There is a splice variant lacking amino acids 22 to 37 that is expressed more strongly in thymocytes. This IL- 4d2 inhibits IL-4 induced T cell proliferation. The IL-4 R is expressed on a wide range of cell types including B and T lymphocytes, monocytes, granulocytes, fibroblasts, endothelial and epithelial cells and expression is induced by IL-4. It promotes differentiation of TH0 cells into Th2 cells. It acts on B cells to promote their division, differentiation, and antibody synthesis. It also acts on endothelium and tissue cells to promote the synthesis of chemokines that selectively attract Th2 cells. (Male, David. Immunology, 7th Edition. C.V. Mosby, 04/24/2006. 8.6). The IL-4 gene is located on human chromosome 5 (along with the IL-3, IL-5, IL-9, IL-13 and granulocyte macrophage colony stimulating factor (GM-CSF) genes) and murine chromosome 11 (along with the IL-3, IL-5, IL-13 and GM-CSF genes). Short or long isoforms of IL-4 can exist arising from alternative splicing. IL-4 is produced by activated T cells, mast cells, basophils and NKT cells and targets many cell types, including B cells, T cells, macrophages and a wide variety of hematopoietic and nonhematopoietic cells. Physiologic signal transduction via IL-4 depends on heterodimerization of the IL-4 receptor a chain (IL-4Ra/CD124), with ?c and possibly the IL-13 receptor a chain (IL-13Ra/CD213a1). IL-4 is the principal cytokine required by B cells to switch to the production of immunoglobulin (Ig)E antibodies, which mediate immediate hypersensitivity (allergic) reactions and help defend against helminth infections. IL-4 also inhibits macrophage activation and most of the effects of IFN-? on macrophages. However, the most important biological effect of IL-4 with respect to immune modulation is the growth and differentiation of Th2 cells. Th2 cells support humoral immunity and serve to downregulate the inflammatory actions of Th1 cells. Moreover, stimuli that favor IL-4 production early after antigen exposure favor the development of Th2 cells. IL-13 is also associated with this subset of T cells. Like IL-4, and along with the fact that it maps closely to IL-4 and shares receptor a subunits with IL-4, IL-13 is expressed by activated T cells, induces IgE production by B cells and inhibits inflammatory cytokine production. These properties of IL-4 and IL-13 have been convincingly demonstrated in mice lacking the IL-4 or IL-13 gene. These mice are deficient in the development and maintenance of Th2 cells.Is a glycoprotein of 15 to 19 kD. There is a splice variant lacking amino acids 22 to 37 that is expressed more strongly in thymocytes. This IL- 4d2 inhibits IL-4 induced T cell proliferation. The IL-4 R is expressed on a wide range of cell types including B and T lymphocytes, monocytes, granulocytes, fibroblasts, endothelial and epithelial cells and expression is induced by IL-4. It promotes differentiation of TH0 cells into Th2 cells. It acts on B cells to promote their division, differentiation, and antibody synthesis. It also acts on endothelium and tissue cells to promote the synthesis of chemokines that selectively attract Th2 cells. (Male, David. Immunology, 7th Edition. C.V. Mosby, 04/24/2006. 8.6). The IL-4 gene is located on human chromosome 5 (along with the IL-3, IL-5, IL-9, IL-13 and granulocyte macrophage colony stimulating factor (GM-CSF) genes) and murine chromosome 11 (along with the IL-3, IL-5, IL-13 and GM-CSF genes). Short or long isoforms of IL-4 can exist arising from alternative splicing. IL-4 is produced by activated T cells, mast cells, basophils and NKT cells and targets many cell types, including B cells, T cells, macrophages and a wide variety of hematopoietic and nonhematopoietic cells. Physiologic signal transduction via IL-4 depends on heterodimerization of the IL-4 receptor a chain (IL-4Ra/CD124), with ?c and possibly the IL-13 receptor a chain (IL-13Ra/CD213a1). IL-4 is the principal cytokine required by B cells to switch to the production of immunoglobulin (Ig)E antibodies, which mediate immediate hypersensitivity (allergic) reactions and help defend against helminth infections. IL-4 also inhibits macrophage activation and most of the effects of IFN-? on macrophages. However, the most important biological effect of IL-4 with respect to immune modulation is the growth and differentiation of Th2 cells. Th2 cells support humoral immunity and serve to downregulate the inflammatory actions of Th1 cells. Moreover, stimuli that favor IL-4 production early after antigen exposure favor the development of Th2 cells. IL-13 is also associated with this subset of T cells. Like IL-4, and along with the fact that it maps closely to IL-4 and shares receptor a subunits with IL-4, IL-13 is expressed by activated T cells, induces IgE production by B cells and inhibits inflammatory cytokine production. These properties of IL-4 and IL-13 have been convincingly demonstrated in mice lacking the IL-4 or IL-13 gene. These mice are deficient in the development and maintenance of Th2 cells.

40. IL-5, originally identified as a B cell differentiation factor, is produced mainly by activated T cells (especially Th2 cells) and aids in the growth and differentiation of eosinophils and late-developing B cells. When IL-5 or CDw125 is absent, mice exhibit developmental defects in certain B cells (CD5+/B-1 B cells) and a lack of eosinophilia upon parasite challenge. IL-5 is a common beta chain cytokines. This group of cytokines utilize the common beta chain (betac/CDw131) in their receptor, including IL-3, IL-5, and GM-CSF. All these genes are closely linked and lie on human chromosome 5. These associated beta chain cytokines overlap in biological function because their common receptor subunit. IL-3 was originally termed muticolony stimulating factor (multi-CSF). It is produced by activated T cells and stimulates both mutipotential hematopoietic cells and developmentally committed cells such as granulocytes, macrophages, mast cells, erythroid cells, eosinophils, basophils and magakaryocytes. Knockout mouse model indicates that mast cells and basophil development upon challenge is affected. GM-CSF was origninally found to stimulate granulocytes and marcrophages. It has been found to be proudced in many cell types, including macrophages, neutrophils, and eosinophils. GM-CSF deficient animals have normal hematopoietic development but suffer from pulmonary disease. IL-5, originally identified as a B cell differentiation factor, is produced mainly by activated T cells (especially Th2 cells) and aids in the growth and differentiation of eosinophils and late-developing B cells. When IL-5 or CDw125 is absent, mice exhibit developmental defects in certain B cells (CD5+/B-1 B cells) and a lack of eosinophilia upon parasite challenge. IL-5 is a common beta chain cytokines. This group of cytokines utilize the common beta chain (betac/CDw131) in their receptor, including IL-3, IL-5, and GM-CSF. All these genes are closely linked and lie on human chromosome 5. These associated beta chain cytokines overlap in biological function because their common receptor subunit. IL-3 was originally termed muticolony stimulating factor (multi-CSF). It is produced by activated T cells and stimulates both mutipotential hematopoietic cells and developmentally committed cells such as granulocytes, macrophages, mast cells, erythroid cells, eosinophils, basophils and magakaryocytes. Knockout mouse model indicates that mast cells and basophil development upon challenge is affected. GM-CSF was origninally found to stimulate granulocytes and marcrophages. It has been found to be proudced in many cell types, including macrophages, neutrophils, and eosinophils. GM-CSF deficient animals have normal hematopoietic development but suffer from pulmonary disease.

41. TGF-beta is prototypic protein of a family that are involved in cell growth, proliferation, differentiation, and apoptosis. The TGF-beta family consists of more than 30 members. TGF-beta 1-3 are particularly interesting as they are remarkably mutifunctional and indispensable. Knockout mouse animal models have shown that deficiency of any of the gene is lethal. TGFbeta1 is the most abundant form of TGF-beta and as such is often referred to as TGF-beta. It was originally identified for its ability to promote the growth of fibroblasts and assigned to chromosome 19 in humans and to chromosome 7 in mice. The human and mouse homologues differ by only one residue in their amino acid sequence. TGF-ß1 is produced by every leukocyte lineage and has profound regulatory effects on a myriad of developmental, physiological and immune processes. In general, TGF-ß1 possesses both pro- and anti-inflammatory activity depending on the presence of other growth factors and the activation or differentiation state of the target cell. For example, at a site of developing inflammation TGF-ß1 can modulate the expression of adhesion molecules, act as a chemoattractant, and orchestrate the immune response by suppressing or activating leukocytes. This orchestration by TGF-ß1 also applies to the Th cell subset paradigm. TGF-ß1 can alter the production of, and response to, cytokines of both Th subsets and can therefore skew Th1 or Th2 immune responses as it sees fit depending on the composition of the inflammatory environment. In fact, TGF-ß1 secretion is a hallmark of a new candidate regulatory T cell subset called Th3 that also secretes IL-4 and IL-10. With such widespread responsibilities, it is no surprise that TGF-ß1 knockout mice exhibit immune dysregulation and succumb to a progressive wasting syndrome shortly after birth. This mortal phenotype is characterized by changes in lymphoid organ architecture, including both the shrinking of the thymus and the swelling of lymph nodes, enhanced proliferation in vivo and defective mitogen responses in vitro. These mice also exhibit massive infiltrations of lymphocytes and macrophages in many organs resembling those found in autoimmune disorders. TGF-ß2, encoded on human and mouse chromosome 1, was originally identified as a suppressor of glioblastoma-derived T cells but is better known for its essential role in the developmental pathways of many tissues. Accordingly, TGF-ß2-deficient mice exhibit perinatal mortality and a wide array of tissue defects including craniofacial, skeletal, heart, eyes, ears and urogenital anomalies. Likewise, TGF-ß3, encoded on human chromosome 14 and mouse chromosome 12, appears to have an important role in certain developmental pathways as evidenced by TGF-ß3-deficient mice that show severe defects in palate and lung morphogenesis and early death.TGF-beta is prototypic protein of a family that are involved in cell growth, proliferation, differentiation, and apoptosis. The TGF-beta family consists of more than 30 members. TGF-beta 1-3 are particularly interesting as they are remarkably mutifunctional and indispensable. Knockout mouse animal models have shown that deficiency of any of the gene is lethal. TGFbeta1 is the most abundant form of TGF-beta and as such is often referred to as TGF-beta. It was originally identified for its ability to promote the growth of fibroblasts and assigned to chromosome 19 in humans and to chromosome 7 in mice. The human and mouse homologues differ by only one residue in their amino acid sequence. TGF-ß1 is produced by every leukocyte lineage and has profound regulatory effects on a myriad of developmental, physiological and immune processes. In general, TGF-ß1 possesses both pro- and anti-inflammatory activity depending on the presence of other growth factors and the activation or differentiation state of the target cell. For example, at a site of developing inflammation TGF-ß1 can modulate the expression of adhesion molecules, act as a chemoattractant, and orchestrate the immune response by suppressing or activating leukocytes. This orchestration by TGF-ß1 also applies to the Th cell subset paradigm. TGF-ß1 can alter the production of, and response to, cytokines of both Th subsets and can therefore skew Th1 or Th2 immune responses as it sees fit depending on the composition of the inflammatory environment. In fact, TGF-ß1 secretion is a hallmark of a new candidate regulatory T cell subset called Th3 that also secretes IL-4 and IL-10. With such widespread responsibilities, it is no surprise that TGF-ß1 knockout mice exhibit immune dysregulation and succumb to a progressive wasting syndrome shortly after birth. This mortal phenotype is characterized by changes in lymphoid organ architecture, including both the shrinking of the thymus and the swelling of lymph nodes, enhanced proliferation in vivo and defective mitogen responses in vitro. These mice also exhibit massive infiltrations of lymphocytes and macrophages in many organs resembling those found in autoimmune disorders. TGF-ß2, encoded on human and mouse chromosome 1, was originally identified as a suppressor of glioblastoma-derived T cells but is better known for its essential role in the developmental pathways of many tissues. Accordingly, TGF-ß2-deficient mice exhibit perinatal mortality and a wide array of tissue defects including craniofacial, skeletal, heart, eyes, ears and urogenital anomalies. Likewise, TGF-ß3, encoded on human chromosome 14 and mouse chromosome 12, appears to have an important role in certain developmental pathways as evidenced by TGF-ß3-deficient mice that show severe defects in palate and lung morphogenesis and early death.

42. GM-CSF was originally found to stimulate granulocytes and macrophages. It is expressed in by many cell types, including macrophages and T cells. GM-CSF shares many functions of IL-3 in stimulating a variety of precursor cells, including macrophages, netrophils, and eosinophils. GM-CSF synergises EPO and TPO to generate erythroid and magakaryocyte progeny. The G-CSF gene is located in the human chromosome 17. It is produced by fibroblasts and monocytes and stimulates granulocyte progenitor cells and neutrohils. The G-CSF receptor is expressed on multipotential hematopoietic progenitor cells and in cells of the myeloid lineage.GM-CSF was originally found to stimulate granulocytes and macrophages. It is expressed in by many cell types, including macrophages and T cells. GM-CSF shares many functions of IL-3 in stimulating a variety of precursor cells, including macrophages, netrophils, and eosinophils. GM-CSF synergises EPO and TPO to generate erythroid and magakaryocyte progeny. The G-CSF gene is located in the human chromosome 17. It is produced by fibroblasts and monocytes and stimulates granulocyte progenitor cells and neutrohils. The G-CSF receptor is expressed on multipotential hematopoietic progenitor cells and in cells of the myeloid lineage.

43. The cytokine network can be depicted in the slide. Cytokines exhibit pleiotropic effects on cell differentiation, proliferation, immune cell activation, tissue development, and homeostasis. They mediate communication among a variety of cell types in the immune system through binding to specific receptors on target cells. Their biological actions vary widely depending on the type of target cells involved. They are endowed with anti-proliferative properties and regulate the synthesis of acute phase proteins following tissue injury, trauma, inflammation, and sepsis. The receptors for a large number of cytokines have been cloned and shown to be membrane-spanning glycoproteins with their amino termini in the extracellular space. Unlike receptors for growth factors, cytokine receptors generally lack identifiable catalytic activity. Most cytokine receptors lack intrisic kinase activity. They transmit their regulatory signals primarily by the receptor associated JAK (Janus kinase) family of tyrosine kinases (type I and type II interferon signaling), or receptor-recruited accessory proteins and kinases (e.g. NFkB signaling). The cytokine network can be depicted in the slide. Cytokines exhibit pleiotropic effects on cell differentiation, proliferation, immune cell activation, tissue development, and homeostasis. They mediate communication among a variety of cell types in the immune system through binding to specific receptors on target cells. Their biological actions vary widely depending on the type of target cells involved. They are endowed with anti-proliferative properties and regulate the synthesis of acute phase proteins following tissue injury, trauma, inflammation, and sepsis. The receptors for a large number of cytokines have been cloned and shown to be membrane-spanning glycoproteins with their amino termini in the extracellular space. Unlike receptors for growth factors, cytokine receptors generally lack identifiable catalytic activity. Most cytokine receptors lack intrisic kinase activity. They transmit their regulatory signals primarily by the receptor associated JAK (Janus kinase) family of tyrosine kinases (type I and type II interferon signaling), or receptor-recruited accessory proteins and kinases (e.g. NFkB signaling).

44. Recognition of antigen in the absence of co-stimulation results in angergy (inability to respond) A T cell requires signals from both the TCR and CD28 for activation. Anergy — in the absence of co-stimulatory molecules inactivation or anergy results. This situation would prevail to tolerize T cells not removed by central tolerance to self antigens expressed on peripheral tissues. No effect — in the absence of an antigen-specific signal (e.g. wrong peptide) there is no effect on the T cell. Activation — co-reception of both signals, from the surface of a professional APC, activates the T cell to produce IL-2 and its receptor (IL-2R). The cell divides and differentiates into an effector T cell, which no longer requires signal 2 for its effector function. Downregulation — at the termination of the immune response, CTLA-4 replaces CD28 and downregulates T cell function. (Male, David. Immunology, 7th Edition. C.V. Mosby, 042006. 7.7.2).Recognition of antigen in the absence of co-stimulation results in angergy (inability to respond) A T cell requires signals from both the TCR and CD28 for activation. Anergy — in the absence of co-stimulatory molecules inactivation or anergy results. This situation would prevail to tolerize T cells not removed by central tolerance to self antigens expressed on peripheral tissues. No effect — in the absence of an antigen-specific signal (e.g. wrong peptide) there is no effect on the T cell. Activation — co-reception of both signals, from the surface of a professional APC, activates the T cell to produce IL-2 and its receptor (IL-2R). The cell divides and differentiates into an effector T cell, which no longer requires signal 2 for its effector function. Downregulation — at the termination of the immune response, CTLA-4 replaces CD28 and downregulates T cell function. (Male, David. Immunology, 7th Edition. C.V. Mosby, 042006. 7.7.2).

46. In 1970, Gershon and Kondo described the finding that T cells not only augmented but also dampened immune responses, and this down-regulation of immune response was mediated by T cells that were different from Th cells, called suppressive T cells. However, the studies on suppressive T cells went silent in the mid 1980s due to lack of molecule biology evidence that was proposed in the research. With the advance of molecular biology, better surface makers and autoimmune disease studies, the CD4+ T cells that suppress both Th1 and Th2 responses were identified, and termed as regulatory T cells, Treg. Tregs are a specialized population of T cells that act to suppress activation of the immune system and maintain immune system homeostasis and tolerance to self-Ag. This population includes naturally produced regulatory T cells (CD4+CD25+Foxp3) and other T cells that have suppresive function. In 1970, Gershon and Kondo described the finding that T cells not only augmented but also dampened immune responses, and this down-regulation of immune response was mediated by T cells that were different from Th cells, called suppressive T cells. However, the studies on suppressive T cells went silent in the mid 1980s due to lack of molecule biology evidence that was proposed in the research. With the advance of molecular biology, better surface makers and autoimmune disease studies, the CD4+ T cells that suppress both Th1 and Th2 responses were identified, and termed as regulatory T cells, Treg. Tregs are a specialized population of T cells that act to suppress activation of the immune system and maintain immune system homeostasis and tolerance to self-Ag. This population includes naturally produced regulatory T cells (CD4+CD25+Foxp3) and other T cells that have suppresive function.

49. Cytokines that promote periodontal tissue destruction Dana Graves Abstract Although periodontal diseases are initiated by bacteria that colonize the tooth surface and gingival sulcus, the host response is believed to play an essential role in the breakdown of connective tissue and bone, key features of the disease process. An intermediate mechanism that lies between bacterial stimulation and tissue destruction is the production of cytokines, which stimulates inflammatory events that activate effector mechanisms. These cytokines can be organized as chemokines, innate immune cytokines, and acquired immune cytokines. Although they were historically identified as leukocyte products, many are also produced by a number of cell types, including keratinocytes, resident mesenchymal cells (such as fibroblasts and osteoblasts) or their precursors, dendritic cells, and endothelial cells. Chemokines are chemotactic cytokines that play an important role in leukocyte recruitment andmay directly or indirectly modulate osteoclast formation. This article focuses on aspects of osteoimmunology that affect periodontal diseases by examining the role of cytokines, chemokines, and immune cell mediators. It summarizes some of the key findings that attempt to delineate the mechanisms by which immune factors can lead to the loss of connective tissue attachment and alveolar bone. In addition, a discussion is presented on the importance of clarifying the process of uncoupling, a process whereby insufficient bone formation occurs following resorption, which is likely to contribute to net bone loss in periodontal disease. J Periodontol 2008;79:1585-1591.Cytokines that promote periodontal tissue destruction Dana Graves Abstract Although periodontal diseases are initiated by bacteria that colonize the tooth surface and gingival sulcus, the host response is believed to play an essential role in the breakdown of connective tissue and bone, key features of the disease process. An intermediate mechanism that lies between bacterial stimulation and tissue destruction is the production of cytokines, which stimulates inflammatory events that activate effector mechanisms. These cytokines can be organized as chemokines, innate immune cytokines, and acquired immune cytokines. Although they were historically identified as leukocyte products, many are also produced by a number of cell types, including keratinocytes, resident mesenchymal cells (such as fibroblasts and osteoblasts) or their precursors, dendritic cells, and endothelial cells. Chemokines are chemotactic cytokines that play an important role in leukocyte recruitment andmay directly or indirectly modulate osteoclast formation. This article focuses on aspects of osteoimmunology that affect periodontal diseases by examining the role of cytokines, chemokines, and immune cell mediators. It summarizes some of the key findings that attempt to delineate the mechanisms by which immune factors can lead to the loss of connective tissue attachment and alveolar bone. In addition, a discussion is presented on the importance of clarifying the process of uncoupling, a process whereby insufficient bone formation occurs following resorption, which is likely to contribute to net bone loss in periodontal disease. J Periodontol 2008;79:1585-1591.

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