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Flashcards in Cytokines Deck (26):
1

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

2

Pyrogen? examples?

-substance that induces fever and elevates body temp

-IL-1- cytokine and endogenous pyrogen

-exogenous sources include endotoxin (gram negative bacteria)

3

Chemotactic factor?

-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

4

Cytokines that mediate and regulate innate immunity?

-type 1 IFNs

-pro inflammatory cytokines (TNF, IL-1, IL-6)

-chemokines

-IL-12

-IL-10

-IL-5, IL-7

5

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

6

Cell source of type 1 interferons?

IFN alpha- predominantly mononuclear phagocytes

IFN beta- probably multiple

7

Type 1 interferon cell targets? receptors?

targets- virtually all

receptors-all IFNs seem to interact with same receptor

8

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

9

What responds to type 1 IFNs?

-oligodenylate synthetase

-dsRNA activated serine/threonine kinase (PKR16)- blocks virus transcription and translation

-RNAses

10

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

11

toxicities of IFNs? (flu symptoms)

-fever

-chills

-malaise

-myalgias

-myelosuppression

-headache

-depression

12

Pro inflammatory cytokines?

-tumor necrosis factor (TNF)

-IL-1

-IL-6

-chemokines

13

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

14

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

15

Prolonged production of TNF can lead to what?

1. wasting of fat and muscle (cachexia)

-appetite suppression

-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)

-intravascular thrombosis

-severe metabolic disturbances (fall in blood glucose levels)

-hypoglycemia in liver

16

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

17

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)

18

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

19

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

20

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

21

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

22

IL-2?

-T cell growth factor

-responsible for progression of activated T lymphocytes from G1 to S phase of cell cycle

-growth, survival, differentiation

23

What produces IL-2? autocrine or paracrine?

-produced by helper T cells

-functions in autocrine and paracrine

-normally produced in response to antigen

24

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

25

what other cytokines is IL-2 redundant with?

IL-15

-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

26

Functions of IFN-gamma?

-stimulates B cell differentiation

-inhibit TH2 cell growth

-activates macrophages

-increases MHC expression on macrophages

-activates NK cells

-antiviral