What are the general properties of cytokines?
1. secretion is brief, self limited event
2. pleiotropism- each cytokine mediates diverse effects
3. redundancy- multiple cytokines may have same function
4. cytokines influence secretion and activity of other cytokines- effects may be additive, synergistic, antagonistic
5. cytokine action may be local or systemic- autocrine, paracrine, endocrine effects
6. cytokines act on specific cell surface receptors - receptor expression is regulated by external signals
7. cell response to cytokines involves change in gene expression- results in acquisition of new function or proliferation
-substance that induces fever and elevates body temp
-IL-1- cytokine and endogenous pyrogen
-exogenous sources include endotoxin (gram negative bacteria)
-substance that serves as an attractant, along a chemical gradient
-receptor mediated- responding cell must express the appropriate receptor in order to respond to particular chemotactic factor
-exogenous- bacterial products for neutrophils
-endogenous- cytokines and chemokine for specific cells
Cytokines that mediate and regulate innate immunity?
-type 1 IFNs
-pro inflammatory cytokines (TNF, IL-1, IL-6)
Properties of type 1 IFN polypeptide?
-about 20 different IFN alpha genes, IFN alpha polypeptide are about 18 kDa
-only one IFN beta gene, IFN beta polypeptide is about 20kDa
Cell source of type 1 interferons?
IFN alpha- predominantly mononuclear phagocytes
IFN beta- probably multiple
Type 1 interferon cell targets? receptors?
targets- virtually all
receptors-all IFNs seem to interact with same receptor
Functions of type 1 interferons?
very important in limiting spread of certain virus infections:
-viruses are most potent stimulator of IFN production (dsRNA triggers TLR-9 activation)
-activated T cells can also stimulate IFN production in mononuclear phagocytes induce signal transduction through JAK/SAT path:
activate receptor associated JAK/SAT kinase path:
-kinase phosphorylate a specific transcriptional factor which moves from the cytoplasm to the nucleus
-transcriptional factor binds to interferon sequence response elements (ISRE) in promoter regions of interferon inducible genes
What responds to type 1 IFNs?
-dsRNA activated serine/threonine kinase (PKR16)- blocks virus transcription and translation
What are the biologic effects of type 1 IFNs?
-inhibit viral replication
-increase expression of class 1 MHC molecules (enhance viral antigen expression to CD8+ CTL)
-enhance production of TH1 in humans (increase IL-12R expression)
-promote sequestration of lymphocytes in lymph nodes (enhance lymphocyte activation by antigens concentrated in the lymph node, especially viral)
-enhance NK cell cytotoxicity
-inhibit proliferation of many cell types in vitro
toxicities of IFNs? (flu symptoms)
Pro inflammatory cytokines?
-tumor necrosis factor (TNF)
Function of TNF? major source? major inducer?
principal mediator of acute inflammatory response to gram negative bacteria (and other infectious microbes)
-systemic complications of severe infection
-also called TNF-alpha
-major source: activated mononuclear phagocytes (also produced by activated T cells, NK cells, mast cells)
-major inducer: LPS
-production augmented by interferon- gamma
Biologic effects of TNF?
1. Activate endothelial cells:
-expression of adhesion molecules such as selections and VCAM-1 and ICAM-1 (bind neutrophils, then monocytes, and lymphocytes)
-secretion of chemokines, also induce chemokine production in macrophages)- enhance affinity of leukocyte integrins for their ligands, and induces leukocyte chemotaxis and recruitment
-production of factors that promote clot formation
2. acts on mononuclear phagocytes to induce IL-1 production
3. stimulates microbicidal activity of neutrophils and macrophages
4. acts on hypothalamus to induce fever- mediated by prostaglandins
5. acts on hepatocytes to induce acute phase of reactants
Prolonged production of TNF can lead to what?
1. wasting of fat and muscle (cachexia)
-reduced synthesis of lipoprotein lipase
2. large amounts lead to:
-myocardial contractility and vascular smooth muscle tone are inhibited (marked fall in blood pressure-shock)
-severe metabolic disturbances (fall in blood glucose levels)
-hypoglycemia in liver
How big are chemokines? how many different ones? classification?
-all are 8-12kD polypeptides containing two internal disulfide loops
-about 40-50 different chemokine
-classified on the basis of number and location of N terminal cysteine residues
what are the two major groups of chemokine?
1. CC: cysteines are adjacent
-act on monocytes, lymphocytes and eosinophils
2. CXC: cysteine residues separated by one amino acid
-act on neutrophils
-CXCL8 (IL-8)- recruits neutrophils from blood to infected area
3. others (C or CXXXC)
Functions of chemokine?
-recruit cells to sites of infection
-regulate traffic of leukocytes and lymphocytes through peripheral lymphoid tissue
-promote angiogenesis and wound healing
-involved in development of diverse lymphoid organs
What is IL-12? what is it made by? key things that it induces/regulates?
-important mediator of early innate immune response to intracellular microbes
-made by mononuclear phagocytes and dendritic cells key inducers/ regulators:
-activator of NK cells
-stimulates IFN-gamma production
-stimulates differentiation of TH cells to TH1
-enhances cytolytic function of NK cells and CD8+ T cells
What is IL-10? what is it made by? key things that it induces/regulates?
-inhibitor of activated macrophages and dendritic cells produced mainly by activated macrophages:
-example of negative regulator
-not clear whether different stimuli act on macrophages to produce IL-10 instead of IL-12 or same stimulus induces production of both but with different kinetics inhibits production of IL-12 by activated macrophages and dendritic cells:
-since IL-12 is an inducer of IFN-gamma and promotes innate and cell mediated immune reaction against intracellular microbes, IL-10 down regulates all these functions
-inhibits expression of co stimulators and class 2 MHC on macrophages and dendritic cells
Lower affinity of IL-10 can predispose a person to what?
inflammatory bowel disease:
-maybe uncontrolled macrophage activation to enteric microbes- suggests an immunomodulatory function
-T cell growth factor
-responsible for progression of activated T lymphocytes from G1 to S phase of cell cycle
-growth, survival, differentiation
What produces IL-2? autocrine or paracrine?
-produced by helper T cells
-functions in autocrine and paracrine
-normally produced in response to antigen
Biologic activity of IL-2?
-autocrine growth factor for T cells
-stimulates growth of NK cells and enhances their cytolytic function
-growth factor for human B cells and stimulus for antibody synthesis
-maintenance of CD4 regulatory T cells
what other cytokines is IL-2 redundant with?
-important growth for survival functions of T cells and NK cells
-made bu mononuclear phagocytes in response to viral infection
-similar structure, same alpha and beta chain receptor
Functions of IFN-gamma?
-stimulates B cell differentiation
-inhibit TH2 cell growth
-increases MHC expression on macrophages
-activates NK cells