Chapter 11 CYTOKINES

Chapter 11 CYTOKINES

group of low molecular weight regulatory proteins secreted by leukocytes as well as a variety of other cells in the body (8~30kD) regulate the intensity and duration of the immune response by stimulating or inhibiting the activation, proliferation, and/or differentiation of various cells (mediate cellular communication) short lived binds with CYTOKINE RECEPTORS JAK-STAT PATHWAY regulates all downstreams of CYTOKINE RECEPTORS

3 MAJOR ROUTES OF CYTOKINE TRAVEL e.x. IL-2 on T cells - clonal expansion

Cytokines, presented according to type of cell that produces them Macrophage T cell

Major cytokines secreted by macrophages

Cytokines secreted by macrophages

Major cytokines secreted by Th1 and Th2 cells

Cytokines produced by Th1 and Th2 cells Inhibit B-cell function

Three main types of effector T cells produce distinct sets of effector molecules, including cytokines

Role of Chemokine: Chemotaxis

Cytokine receptors Necessary for specific cytokine action There is redundancy in cytokine receptor usage Gamma chain used in several cytokine receptors binding of receptor transduces signal in cell that results in production of transduction factors and, ultimately, gene expression Stimulate altered pattern of gene expression in target cell, including expression of other cytokines

MOST CYTOKINE RECEPTORS ARE IN 2 CLASSES CLASS I CYTOKINE RECEPTORS Most of the cytokine-binding receptors that function in the immune and hematopoietic systems belong to this receptor family. There are conserved amino acid sequence motifs in the extracellular domain - 4 positionally conserved Cys residues (CCCC) and a conserved sequence of Trp-Ser-X-Trp-Ser (WSXWS) where X is a nonconserved amino acid. The receptors consist of 2 polypeptide chains: a cytokine-specific subunit and a signal-transducing subunit which is usually not specific for the cytokine. In a few cases these receptors are trimers. The signal transducing subunit is required for high affinity binding of the cytokine. CLASS II CYTOKINE RECEPTORS These receptors possess the conserved cysteine motifs, but lack the WSXWS motif present in class I cytokine receptors. The IFNs bind to Class II receptors.

Structural features of the five types of cytokine receptors FIGURE 11.5. Structural features of five types of cytokine receptors. Many contain highly conserved cysteine residues.

Structural features of Class I cytokine receptors Common r-chain (mediates intracellular signaling): FIGURE 11.6. Structural features of members of class I cytokine receptor family that share common chain (green) that mediates intracellular signaling.

IL-2 receptor complex: receptor; betagamma is low affinity complete trimer of alpha-betagamma is high affinity receptor

FIGURE 11.7. Comparison of two forms of IL-2 receptors expressed on cells.

Cytokines differ from growth factors in the structure of the receptor. IGF-1R Has Tyr kinase domain IL-6R Lacks Tyr kinase domain JAK (a kinase) docks instead

Selected cytokines and their functions Immunoregulatory cytokines (major source is CD4 Tcell) : IL-2, IL-4, IL-12, IFNr, IL10, TGF-b, IL5. Innate immune related cytokines (Pronflammatory cytokines) : IL-1, IL-6, TNF-a, IFN-a, IFN-b.

1. Immunoregulatory cytokines (major source is CD4 Tcell) : IL-2, IL-4, IL-12, IFNr, IL10, TGF-b, IL5.

2. Innate immune related cytokines : IL-1, IL-6, TNF-a, IFN-a, IFN-b. The role of endogenous pyrogens (IL-1, IL-6, TNF-a) Cause fever Production of acute phase proteins (inflammation) Increase in circulating neutrophiles

Interferons ( IFN-a, IFN-b ) So named because of initial discovery of protein s action of interference with viral replication and prevent the spread of viruses to uninfected cells.

Interferons are anti-viral proteins produced by cells in response to viral infection

Tumor necrosis factors (TNF) So named because of action of one type of TNF against tumor cells

Cytokine modulation Mechanisms of control of cytokine activities Cytokine modulation of physiological processes

Mechanisms of control of cytokine activities: (Inhibitor or Antagonist) antagonist IL-2, 4, 6, 7, IFN-r And TNF

Chemokines Family of chemo-attractant cytokines Small proteins Guide cells to site of infection Receptors are membrane proteins with 7 membrane-spanning helices (helixes)

Four important biological functions of chemokines

Selected chemokines and their functions

Neutrophil migration Important aspect of innate immunity Modulated by cytokines Migration from circulation to tissues, for action

Neutrophil chemotaxis and transendothelial migration