Module 13: Cytokines

cytokines

proteins that mediate the effector functions of the immune system

Cytokines are involved in

inflammatory response
hematopoiesis
clonal expansion of T cells
proliferation and differentiation of B cells
activation of NK cells, cytotoxic T-cells, B-cells, neutrophils, eosinophils, mast cells

Characteristics of cytokines

are soluble proteins
have low molecular mass
secreted by a large number of different cell types
regulate many important biological processes
mediate cell-cell communication in the immune response
regulation intesity and duration of the immune response
are not hormones

Lymphokines

cytokines released by lymphcytes

monokines

cytokines released by monocytes and macrophages

interleukins

leukocytes that act on other leukocytes

chemokines

cytokines with chemotactic activity

autocrine

the target cell is the same cell that released the cytokine

paracrine

the target cell is in close proximity to the cell that released the cytokine

endocrine

the target cell is distant from the cell that released the cytokine

Pleiotrophy

a given cytokine has different biological activities on different target cells

redundancy

two or more cytokines mediate similar biological function

synergy

combined effect of two cytokines is greater than additive effects of individual cytokines

antagonism

effect of one cytokine inhibits or reduces the effect of another cytokine

Cascade induction

effect of one cytokine induces the target cell to produce a cytokine which in turn acts on other target cells to produce cytokines

Macrophages and Th cells

two major producers of cytokines

What prevents cytokines from activating cells in a nonspecific manner during an immune response

expression of specific receptors by target cells
localized effective concentration
short half-life

cytokines of innate immunity

IL-1, TNF-alpha, IL-6

Cytokines of Adaptive immunity

IL-4, IL-5, IFN-gamma

Cytokines of the IL-1 family

promote inflammation (proinflammatory cytokines)
secreted very early in immune responses by monocytes, macrophages, and dendritic cells

IL-1 receptor antagonist (IL-1RA)

binds to IL-1RII and prevents it from binding with its functional partner IL-1RAcP

Class I family cytokines

hematopoietin family
common feature is multiple subunits
common subunits paired with distinct cytocike binding subunit to form subfamilies of receptors

IL-2R

Class I family gamma chain bearing subfamily
exists in low, intermediate, and high-affinity forms
different forms are marked by the presence of accessory receptor chains
lymphocytes shift to expression of high-affinity form during activation events

IL-R beta gamma

Resting T-cells express beta and gamma chains

alpha-chain

activated ells express the __ of IL-R

IL-R trimeric high affinity

expressed only in activated CD4+ and CD8+ T-cells

intermediate affinity IL-2R

IL-2R beta and IL-2R gamma
expressed by NK cells and resting T cells

High affinity IL-2R

IL-2R alpha, IL-2R beta, IL-2R gamma
expressed by activated CD4+ and CD8+ T cells and activated B cells

Low affinity IL-2R

IL-2R alpha
expressed by activated CD4+ and CD8+ T cells and activated B cells

GM-CSF/Beta-chain bearing subfamily

Class I family cytokines
includes receptors for IL-3, IL-5 and GM-CSF
each cytokine binds to a unique alpha subunit
the beta subunit is shared signal-transducing protein
these cytokines exhibit redundeancy

IL-6/Gp130 receptor subfamily

includes IL-6 and IL-12 receptors
critically important; targeted distribution is lethal in embronic mice
ligand-specific dimers or trimers are expressed with the gp130 subunit

Type I interferons

Class II cytokine family
antiviral effects
secreted by activated macrophages and dendritic cells
interferons alpha and beta

Type II interferon (aka interferon gamma)

Class II cytokine family 
dimer produced by activated T/NK cells
potent modulator of adaptive immunity

Type III interferon family

Class II cytokine family
interferon lambda 3 and 4
secreted by plasmacytoid dendritic cells, controls viral infection
receptros for IFN lamdba is expressed by epithelial cells of GI, respiratory and blood-brain barrier

Th1 Cytokines

IL-2
IFN-gamma
TFN-Beta
GM-CSF
IL-3

Th2 cytokines

IL-3
IL04
IL-5
IL-10
IL-13

Th1

delayed type hypersensitivity
macrophage activation
promotopn of opsonin-complement fixing antibody

Th2

eosinophil activation
Help B cell function
IgM, IgE and non-complement activating IgG isotype

Endotoxin

LPS in the bacerial cell wall stimulates macrophages to over produce IL-1 and TFN-alpha

Bacterial Septic shock symptoms

fever
drop in blood pressure
diarrhea
widespread blood clotting in various organs which is often fatal condition

cytokine storm

release of a large amount of pro-inflammatory cytokines such as IL-1, IL-6, TFN-alpha and interferons
caused by a wide variety of infections and noninfectious diseases and also by some therapeutic approaches

Local infection

TFN-alpha indiced endothelial cell to produce platelet activating factor (PAF)
PAF triggers blood clotting - prevent pathogen from entering blood stream

Systemic infection

TFN-alpha is released from the liver, spleen and other sites
systemic releases causes vasodilation, loss of plasma volume due to increased vascular permeability, massive clotting in small blood vessels frequently leading to organ failure

Lepromatous leprosy

low Th1 activity, high Th2 activity

Tuberculoid Leprosy

High Th1 activity, intermediate Th2 activity