35: Cytokines

Leukotriene that is specifically important for leukocyte recruitment, rolling, and adhesion

LTB₄

PAF

Platelet activating factor; potent mediator that increases vascular permeability longer than histamine

Role of cytokines

Systemic/immune messenger molecules

Source of most of the cytokines

• Macrophages

• Lymphocytes

• Dendritic cells

Most important innate immunity cytokines for acute inflammation

TNF and IL-1

Primary source of TNF and IL-1

M1

Key functions of TNF and IL-1

• Responsible for the systemic signs of acute inflammation

• Activates endothelium and leukocytes

What does it mean that TNF and IL-1 activate endothelium

They increase the expression of adhesion molecules and encourage coagulation

How does TNF activate leukocytes

Induces NO production for oxygen-dependent killing via reactive nitrogen species

How does IL-1 activate leukocytes

• Activates T_H cells to T_H17

• Activates fibroblasts

Systemic effects of TNF

• Suppresses appetite

• Encourages protein catabolism

• Fever, but not the main cause

Systemic effects of IL-1

Primary inducer of fever

How does IL-1 cause a fever

Induction of prostaglandin production from the hypothalamus

T_H cell that is anti-inflammatory

T_reg

Autocrine

Cell releases a signal that acts on itself

Paracrine

Cell releases a signal that acts on a neighboring cell

Endocrine

Cell releases a signal that acts on a very distant site, traveling via the blood

Types of endocrine signaling molecules

Hormones and cytokines

Chemokines

Subset of cytokines that facilitates WBC chemotaxis, among other things

Chemokine that attracts neutrophils

IL-8

What happens if there is a LOT of IL-8

Induces NETosis of neutrophils

Chemokine that attracts eosinophils

Eotaxin

Primary plasma-derived mediator of inflammation

Complement

Source of plasma-derived mediators of inflammation

LIVER (where else, honestly)

Primary function of complement

Pretty specific for defense against bacterial/microbial infections

Actions of complement activation

• Increased vascular permeability

• Chemotaxis

• Opsonization

Complement mechanism for increasing vascular permeability

C3a and C5a (anaphylatoxins) cause histamine release

Complement mechanism for chemotaxis

C5a activates LOX, which helps with more chemotaxis (leukotrienes!)

Complement mechanism for opsonization

C3b is an opsonin

Three pathways of complement activation

• Classical

• Alternative

• Lectin

Whatever the mechanism of activation, where do all the complement pathways converge

C3 convertase

Complement pathway that is part of the adaptive immunity

Classical pathway

Activation of the alternative pathway

Complement physically encountering the insulting microbial molecule

Activation of the classical pathway

Ag:Ab complex

Activation of the lectin pathway

Contact with mannose in bacterial walls

What happens once the pathways get to C3 convertase

It splits into C3a (anaphylatoxin) and C3b (butter!)

Action of C3b

Opsonin, also splits C5 to C5a and C5b

Action of C5a

Anaphylatoxin

Action of C5b

Binds up C6-9 to form the MAC

Function of bradykinin

Neurotransmitter that is vasoactive and suspected to be part of producing pain

Plasma products of coagulation that are involved in inflammation

• Fibrin

• Thrombin

• Tissue factor

Other miscellaneous plasma derived inflammatory mediators

• Neuropeptides

• Substance P