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Lecture 17 Cytokines. What are cytokines?. A collection of polypeptides used for communications between cells Play role similar to hormones (messengers of the endocrine system) Hormones usually act at a distance Cytokines act locally

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Lecture 17 Cytokines


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what are cytokines
What are cytokines?
  • A collection of polypeptides used for communications between cells
  • Play role similar to hormones (messengers of the endocrine system)
    • Hormones usually act at a distance
    • Cytokines act locally
  • Differ from growth factors that are produced constitutively, while cytokine production is carefully regulated
  • Play an important role in both innate and adaptive immunity
cytokine nomenclature
Cytokine nomenclature
  • Interleukins (1-18)
  • Interferons (a,b,g)
  • Others (common names)
cytokine mediated effects
Cytokine -mediated effects
  • Cell growth
  • Cell differentiation
  • Cell death
  • Induce non-responsiveness to other cytokines/cells
  • Induce responsiveness to other cytokines/cells
  • Induce secretion of other cytokines
how do cytokines tell cells what to do
How do cytokines tell cells what to do?
  • Produced by cells as part of normal cellular activity and/or the result of environmental trigger
  • Bind to receptors on cells
  • Trigger signal transduction pathways
  • Initiate synthesis of new proteins
properties of cytokines
Properties of cytokines
  • Proteins
  • Low molecular weight
  • Bind to receptor on either cell which produced it or another cell
  • Receptor binding triggers a signal
  • Signal results in altered pattern of gene expression
cytokines can act in three different manners
Cytokines can act in three different manners
  • Autocrine
    • Cytokine binds to receptor on cell that secreted it
  • Paracrine
    • Cytokine binds to receptors on near by cells
  • Endocrine
    • Cytokine binds cells in distant parts of the body
cytokine actions
Cytokine Actions
  • Pleiotropy
    • Act on more than one cell type (INFa/b)
  • Redundancy
    • More than one cytokine can do the same thing (IFNa/b and IFN)
  • Synergy
    • Two or more cytokines cooperate to produce an effect that is different or greater than the combined effect of the two cytokines when functioning separately (IL-12 and IL-8)
  • Antagonism
    • Two or more cytokines work against each other (IL-4 and IL-12)
how can non specific cytokines act specifically
How can non-specific cytokines act specifically?
  • Only cells expressing receptors for specific cytokines can be activated by them
  • Many cytokines have very short half-lives
    • Only cells in close proximity will be activated
  • High concentrations of cytokines are needed for activation
    • Only cells in close proximity will be activated
    • May require cell-to cell contact
five cytokine receptor families
Five cytokine receptor families
  • Immunoglobulin superfamily receptors
  • Class I cytokine receptor family (hematopoietin receptors)
    • Binds most of the cytokines in the immune and hematopoietin systems
  • Class II cytokine receptor family
  • TNF receptor family
  • Chemokine receptor family
cytokines regulate the immune response
Cytokines regulate the immune response
  • Cells with the appropriate receptors become activated
    • To differentiate
    • To express receptors which will make them receptive to other cytokines
    • To secrete other cytokines
signal transduction by cytokine receptors
Signal Transduction by cytokine receptors
  • Cytokine receptors on different cell types trigger different events
  • How do you get the message from the outside of the cell to the machinery inside?
involvement of cytokines in the immune response
Alert to infection.tumor/etc.

Recruit cells to site

Specify type of immune response

Immune effector phase

Immune down-regulation

Immune memory and resetting the system

Early mediators (IFNa/b)

Chemokines (MIP-1a)

Early & late mediators (IL-2, IFNg, IL-4, IL-5)

Down-regulators (IL-10, TNFg)

Maintenance of cytokines, etc. (GM-CSF, IL-3, IL-7, etc.)

Involvement of cytokines in the immune response
early mediators
Early mediators
  • Interferons a/b
    • Induced by dsRNA, etc.
    • Induced by CD40/CD40L pathway
    • IFNs can induce more of themselves
    • Directly interferes with viral replication
    • Activation of T and NK cells
chemokines
Chemokines
  • Recruit to sites of infection
  • MIP-1a (NK and T cells)
  • MIG, RANTES (CD4+T cells)
  • IL-8 (neutrophils)
  • Eotaxin (eosinophils)
early mediators18
Early mediators
  • IL-12, IL-15, 1l-18, IFN-g (from NK cells), IL-10
  • Proinflammatory mediators
  • Produced by cell associated with innate immunity (macrophages, NK, etc.)
  • Mediate direct effects
  • Promote inflammation
  • Shape downstream responses
late mediators
Late mediators
  • IL-2, IL-4, IL-5, IFN-g, TNF, IL-6, IL-10
  • Produced by cells of the adaptive immune response (T and B cells)
  • Direct effects
  • More immunoregulatory functions
cytokine secretion and biological activities of t h 1 and t h 2 subsets
Cytokine secretion and biological activities of TH1 and TH2 Subsets

Type 1

Type 2

Cell-mediated

Immune response

(intracellular

Organisms)

Humoral

response

(parasites)

T cell

IL-2

IFN-g

TNF

IL-4

IL-5

down regulators
Down regulators
  • IL-10, IL-11, TGF-b
  • Inhibit proliferation, cytokine production
  • Produced by both innate and adaptive cells
maintenance cytokines
Maintenance cytokines
  • GM-CSF, IL-3, IL-7, IL-9, etc.
  • Induce cell differentiation, cell growth
cytokine cross regulation
Cytokine cross-regulation
  • In a a given immune response, either TH1 or TH2 response dominates
  • Cytokines of one response tend to down-regulate the other type of response
  • Example: TH1 cells secrete IFN-g, which inhibits proliferation of TH2 subset
role of t h 1 t h 2 balance in determining disease outcomes
Role of TH1/TH2 balance in determining disease outcomes
  • Balance of two subset determines response to disease
  • Leprosy
    • Tuberculoid (TH1, CMI response, patient lives)
    • Lepromatous (TH2, humoral response, patient dies)
cytokine related diseases
Cytokine-related diseases
  • Bacterial septic shock
    • Blood pressure drops, clots form, hypoglycemia ensues, patient dies
    • LPS triggers results in TNF release
    • TNF induces IL-1 which induces IL-6 and IL-8
  • Bacterial toxic shock and related diseases
    • Superantigens trigger large numbers of T cells which release massive amounts of cytokines (Super antigens are bacterial toxins that bridge CD4 T cell receptors and the MHC class II molecules on APC’s, bypassing the need for antigen)
  • Lymphoid and myeloid cancers
    • Some cancer cells secrete cytokines
  • Chagas’ disease
    • Trypanosoma cruzi infection results in sever immune suppression
    • Depression of IL-2 receptor production
components of the immune system

Intra- and Extracellular Inflammatory Mechanisms to Destroy or Inactivate Pathogens

Components of the immune system

Help



T cell

CD4



T cell

CD8



T cell

B cell

Inflammatory

cytokines

Cytotoxic T cells

?

Antibody

Interferon &

Non-lymphoid

Cytokines

Macro-

phages

Complement

Granulo-

cytes

Adapted from Marrack and Kappler, 1994

infectious agents that target cytokines
Infectious agents that target cytokines
  • Epstein-Barr virus foster the generation of T helper cells that do not produce IL-2.
  • EBV produces an analog of IL-10 that favors TH2 cells, rather than TH1.
  • Parasites such as tape worms induce high levels of IgE, an immunoglobulin induced by TH2 cells.
  • Since TH1 cells mediate inflammation, this may be a protective ploy to avoid destructive inflammatory processes.
immunosuppressive effects of oral bacteria on immune function
Immunosuppressive effects of oral bacteria on immune function
  • Impairment of B and T cell function (P. intermedia, P. asaccharolytica, P. endodontalis, P. melaninogenica)
  • Production of specific toxins that kill monocytes (A. actinomycetemcomitans)
  • Provoke the release of peroxide, prostaglandins and other mediators capable of inhibiting lymphocyte function (T. denticola)
  • Modulate expression of cytokines
cytokine inducing components of periodontopathogens
Cytokine-inducing components of Periodontopathogens
  • Taken from Wilson, M., Reddi, K., Henderson, B. 1996. Cytokine-inducing components of periodontopathogenic bacteria. J. Periodont. Res.31:393-407.
  • Pro-inflammatory cytokines such as interleukin (IL)-1, IL-6, IL-8 and tumor necrosis factor (TNF) are believed to be the major pathological mediators of inflammatory diseases ranging from arthritis to periodontal diseases.
  • It is believed that components of microorganisms have the capacity to induce cytokine synthesis in host cells.
cytokines produced by host cells in response to components products from periodontopathogens
Cytokines produced by host cells in response to components/products from periodontopathogens
interferon action
Interferon Action
  • Viral replication stimulates the infected host cell to produce interferon.
  • Interferon induces uninfected cells to
    • produce antiviral proteins that prevent translation of viral mRNA
    • degrade viral nucleic acid
  • Viral replication is blocked in uninfected cells
therapeutic uses of cytokines
Therapeutic uses of cytokines
  • Modulation of TH activation
  • Interfere with receptor function
  • Interfere with cytokine
    • Make it unable to bind to receptor
    • Make it unable to act
examples of therapeutic uses
Examples of therapeutic uses
  • Soluble T-cell receptor
  • Anti-IL-2R
  • Interleukin analogs which bind receptor, but do not trigger activation (ties up receptor)
  • Toxins conjugated to cytokines which kill activated T-cells
  • Administration of cytokines to enhance immunity (side effects/ short half lives)
  • Allergies