Cytokine Messenger Systems Flashcards
Pathway of Cytokine Signaling
Cytokines bind to homodimeric or heterodimeric receptors which are constitutively bound to JAKs.
Conformational change in the receptor allows trans- and/or auto-phosphorylation of the two bound JAKs.
These in turn phosphorylate the cytokine receptors.
STAT proteins bind to phosphorylated chains allowing JAKS to phosphorylate the STATs.
Phosphorylated STATs form dimers and translocate to nucleus, regulating gene expression.
Cytokines play a critical role in:
Inflammatory reactions, linking of innate and adaptive immunity, activation of T cells (Th1/Th2 polarization), activation of B cells and Ab production (isotype switching), and important control of hematopoiesis.
Cytokines are pleiotropic, which means:
exhibit multiple effects on growth and differentiation of a variety of cell types
Properties of Cytokines: Redundancy
Activated Th cells –> IL-2, IL-4, IL-5 –> B cell proliferation
Properties of Cytokines: Synergy
Activated Th Cells –> IL-4 + IL-5 –> B cell induced class switch to IgE
Properties of Cytokines: Antagonism
Activated Th cells: IFN-y blocks B cell class switch to IgE induced by IL-4
Properties of Cytokines: Cascade
Activated Th cells –> IFN-y –> Macrophage –> IL-12 –> Activated Th cells –> IL-2, IFN-y, TNF-B, and others
TNF
Principle Cell Source: Macrophages and T cells
Targets and Biologic Effects: Endothelial cells: activation (inflammation, coagulation), Neutrophils: activation, Hypothalamus: fever, Liver: synthesis of acute phase proteins, Muscle and fat: catabolism, many cell types: apoptosis.
Endotoxin (LPS) is most potent inducer of TNF.
TNF is primary mediator of septic shock.
Potent activator of neutrophils.
Binds to TNF receptor I and TNF receptor II.
TNF induces antitumor immunity through direct cytotoxic effects (apoptosis) of cancerous cells.
IL-1
Principle cell source: Macrophages, endothelial cells, some epithelial cells.
Targets and effects: Endothelial cells: activation (inflammation and coagulation), Hypothalamus: fever, Liver: synthesis of acute phase proteins.
Interacts w/ CNS to produce fever, lethargy, sleep, and anorexia.
Stimulates ICAM-1, VCAM-1, and E-selectin on endothelial cells, but is SECOND IN LINE after TNF-a.
Shares activities with TNF.
Only IL-1 induces production of IL-2 by, and proliferation of, CD4 T lymph.
Can be neutralized by IL-1ra.
Chemokines
Principle Cell source: Macrophages, endothelial cells, T lymph, fibroblasts, and platelets
Targets and Effects: Leukocytes (chemotaxis and activation)
IL-12
Principle Cell Source: Macrophages and DCs
Targets and Effects: NK cells and T cells: IFN-y synthesis, increased cytolytic activity, T cells: Th1 differentiation.
Heterodimer that consists of IL-12p40 and IL-12p35.
Controls cell-mediated immunity via activation of Th1 cells.
Stimulates IFN-y production and induces proliferation, cytotoxicity, and cytokine production of NK cells.
Synergizes with IL-18 for IFN-y release.
IFN-y
Principle Cell Source: NK cells and T lymph
Targets and Effects: Activation of macrophages, stimulation of some Ab responses
Critical for innate and adaptive immunity.
Most important cytokine for cell-mediated immunity.
Major activator of intracellular killing of pathogens by Macrophage by stimulating phagocytosis, secretion, respiratory burst, and NO production.
Stimulates killing by NK cells and neutrophils.
Stimulates expression of MHC class I and II.
Stimulates Ag presentation by APCs.
Stimulates cytokine production by APCs.
Stimulates expression of ICAM-1.
Inhibits allergic responses by suppressing many IL-4 mediated effects.
Has modest antiviral activity unlike type I interferons IFN-a and IFN-B.
IFN-a, IFN-B
Principle Cell Source: IFN-a: Macrophages, IFN-B: Fibroblasts
Targets and Effects: All cells: antiviral state, increased class I MHC expression, NK cells: activation
IL-10
Principle Cell Source: Macrophages and T cells (mainly Th2)
Targets and Effects: Macrophages: inhibition of IL-12 production, reduced expression of costimulators and class II MHC molecules.
Important immuno-regulatory cytokine.
Inhibits production of IL-1B, IL-6, IL-8, IL-12, and TNF-a.
Inhibits class II MHC expression by APCs.
Inhibits co-stim molecules CD80 and CD86 by APCs.
Inhibits production of IFN-y and TNF-B by Th1 lymph.
Inhibits production of IL-4 and IL-5 by Th2 lymph.
Controls tolerance to environmental allergens.
IL-6
Source: Macrophages, endothelial cells, T cells
Targets and effects: Liver: synthesis of acute phase proteins, B cells: proliferation of Ab-producing cells.
Most important inducer of acute-phase proteins.
Shares activities w/ IL-1 such as pyrexia (fever) but IL-1 is more important.
IL-6 stimulates differentiation of B lymph to mature plasma cells producing Abs.
Primary role in Th17 immune regulation.
IL-15
Source: Macrophages and others
Targets and effects: NK cells and T cells: proliferation
Most important activity is activation of NK cells.
T-cell growth factor.
Chemotactic for T lymph.
Very important for survival of CD8 memory T cells.
IL-18
Source: Macrophages
Targets and Effects: NK cells and T cells: IFN-y synthesis
