Cytokines Flashcards
1
Q
What are the general properties of cytokines?
A
- secretion is brief, self limited event
- pleiotropism- each cytokine mediates diverse effects
- redundancy- multiple cytokines may have same function
- cytokines influence secretion and activity of other cytokines- effects may be additive, synergistic, antagonistic
- cytokine action may be local or systemic- autocrine, paracrine, endocrine effects
- cytokines act on specific cell surface receptors - receptor expression is regulated by external signals
- cell response to cytokines involves change in gene expression- results in acquisition of new function or proliferation
2
Q
Pyrogen? examples?
A
- substance that induces fever and elevates body temp
- IL-1- cytokine and endogenous pyrogen
- exogenous sources include endotoxin (gram negative bacteria)
3
Q
Chemotactic factor?
A
- 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
Q
Cytokines that mediate and regulate innate immunity?
A
- type 1 IFNs
- pro inflammatory cytokines (TNF, IL-1, IL-6)
- chemokines
- IL-12
- IL-10
- IL-5, IL-7
5
Q
Properties of type 1 IFN polypeptide?
A
- 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
Q
Cell source of type 1 interferons?
A
IFN alpha- predominantly mononuclear phagocytes
IFN beta- probably multiple
7
Q
Type 1 interferon cell targets? receptors?
A
targets- virtually all
receptors-all IFNs seem to interact with same receptor
8
Q
Functions of type 1 interferons?
A
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
Q
What responds to type 1 IFNs?
A
- oligodenylate synthetase
- dsRNA activated serine/threonine kinase (PKR16)- blocks virus transcription and translation
- RNAses
10
Q
What are the biologic effects of type 1 IFNs?
A
- 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
Q
toxicities of IFNs? (flu symptoms)
A
- fever
- chills
- malaise
- myalgias
- myelosuppression
- headache
- depression
12
Q
Pro inflammatory cytokines?
A
- tumor necrosis factor (TNF)
- IL-1
- IL-6
- chemokines
13
Q
Function of TNF? major source? major inducer?
A
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
Q
Biologic effects of TNF?
A
- 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 - acts on mononuclear phagocytes to induce IL-1 production
- stimulates microbicidal activity of neutrophils and macrophages
- acts on hypothalamus to induce fever- mediated by prostaglandins
- acts on hepatocytes to induce acute phase of reactants
15
Q
Prolonged production of TNF can lead to what?
A
- wasting of fat and muscle (cachexia)
- appetite suppression
- reduced synthesis of lipoprotein lipase - 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
Q
How big are chemokines? how many different ones? classification?
A
- 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
Q
what are the two major groups of chemokine?
A
- CC: cysteines are adjacent
- act on monocytes, lymphocytes and eosinophils - CXC: cysteine residues separated by one amino acid
- act on neutrophils
- CXCL8 (IL-8)- recruits neutrophils from blood to infected area - others (C or CXXXC)
18
Q
Functions of chemokine?
A
- 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
Q
What is IL-12? what is it made by? key things that it induces/regulates?
A
- 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
Q
What is IL-10? what is it made by? key things that it induces/regulates?
A
- 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
Q
Lower affinity of IL-10 can predispose a person to what?
A
inflammatory bowel disease:
-maybe uncontrolled macrophage activation to enteric microbes- suggests an immunomodulatory function
22
Q
IL-2?
A
- T cell growth factor
- responsible for progression of activated T lymphocytes from G1 to S phase of cell cycle
- growth, survival, differentiation
23
Q
What produces IL-2? autocrine or paracrine?
A
- produced by helper T cells
- functions in autocrine and paracrine
- normally produced in response to antigen
24
Q
Biologic activity of IL-2?
A
- 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
Q
what other cytokines is IL-2 redundant with?
A
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
Q
Functions of IFN-gamma?
A
- stimulates B cell differentiation
- inhibit TH2 cell growth
- activates macrophages
- increases MHC expression on macrophages
- activates NK cells
- antiviral
