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Complement and Mediators of Inflammation. Lecture C4-06M Thursday, November 7, 2002 S TEPHEN R. J ENNINGS , P H .D. Redness. Heat. Pain. Swelling. Overview Of Inflammation. Classic Signs: Swelling, Redness, Heat, Pain, Altered Function. The Complement (C’) System.

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Complement and Mediators of Inflammation

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Complement and

Mediators of

Inflammation

Lecture C4-06M

Thursday, November 7, 2002

STEPHEN R. JENNINGS, PH.D.


Redness

Heat

Pain

Swelling

Overview Of Inflammation

Classic Signs: Swelling, Redness, Heat, Pain, Altered Function


The Complement (C’) System

The Complement system consists of a complex series of fifteen proteins, many of which are proteineases.

It is a primitive form of defense against infection, being conserved throughout evolution.

It performs three vital functions:

cell activation

cytolysis

opsonization.

Is one of the first systems activated in the response to infection.

The Complement system can be considered as a cascade of interacting proteins, acting in a defined manner, resulting in the initiation of important innate biological effects.


Pathways of Complement

Activation


Pathways of Complement

Activation


The Classical Pathway

C1qrs Complex


The Classical Pathway

C1qrs binds Fc region of IgG


The Classical Pathway

Formation of the Classical C3 Convertase


The Classical Pathway

Formation of the Classical C3 Convertase


The Alternative Pathway

Formation of Alternative C3 Convertase


The Alternative Pathway

Formation of Alternative C3 Convertase


Formation of the C5

Convertases


Formation of the Membrane

Attack Complex (MAC)


Terminal Complement Components


Biological Functions of

Complement


Complement Components and

Inflammation


Overview of Complement-mediated

Biological Effects


Regulation of

Complement Activation


Regulation of

Complement Activation


Mediators of Inflammation

FunctionMediators

Increased vascular permeabilityHistamine, bradykinin, C3a, C5a, PGE2,

prostacyclins, Hageman factor.

Vasoconstriction Thromboxane A2, leukotrienes C and D, C5a,

LTB4, formyl peptides

Smooth muscle contractionC3a, C5a, histamine, LTB4,

leukotrienes C and D, thromboxane A2, bradykinin

Increased endothelial cell stickinessIL-1, TNF-a, endotoxin, LTB4

Pyrogens (Fever induction)IL-1, TNF-a, PGE2

PainPGE2


Lipid Mediators of Inflammation

Metabolites of Membrane Phospholipids


The Coagulation Pathway


Cytokines in Inflammation


Actions of TNF-a


Proinflammatory Cytokines


Function of IL-8

(Chemokine)


Signaling through

Chemokine Receptors


Leukocyte Adhesion and

Extravasation


Overview Of Inflammation


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