CYTOKINES and CYTOKINE RECEPTORS.pdf

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CYTOKINES/CYTOKINE RECEPTORS
Ch.8:15-8:29 Janeway/Travers Ch 12, Abbas Text
I.
Methods of Cell Communication -- concept of the "immunological synapse".
A.
Cognate - cell/cell contact
B.
Non-Cognate - "soluble messengers"
1.
Reality is mixture of both
2.
Initially termed "factors"; i.e. TCGF, BCGF
a.
Lymphokine - "lymphocyte moving molecules"
b.
Monokine - "monocyte moving molecules"
c.
Cytokine - "cell moving molecules"
d.
Interleukins (IL) - "molecules that move between cells"
(1) To get IL - must be cloned/well characterized -- presently up to IL-
18; along with a variety of others that retained original names
(2) Probably about a dozen will cover the majority of important
activities since there is considerable overlap, i.e. "backup"
3 General properties of cytokines
a. Pluripotent molecules which almost invariably have a wide range of activities on
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diverse cell types
b. Produced during the effector phases of natural and specific immunity – mediate
and regulate immune and inflammatory responses.
c. Produced during the effector phases of natural and specific immunity – mediate
and regulate immune and inflammatory responses.
d. Often considerable redundancy
e. Often considerable redundancy
f. Work locally rather than systemically.
C.
Concept of autocrine vs. paracrine stimulation
II. Inflammatory Cytokines - Cytokines That Mediate Natural Immunity:
IL-1a,b
Mf, Other
T, Endot,, Brain
Acute Phase Rx,
Fever, Costim.
TNFa,b
Mf, T
PMN, Endot. Brain,
Liver, T
Multiple
IL-6
Multiple
T, B, plasma cells,
Liver
Multiple – esp
Pl. Cell
IL-8
Multiple
PMN
chemotaxis
TypeI IFN
a,b
Mf, Fib.
All
Antiviral,
MHC I
Inc.
A.
IL-1 [(LAF - pyrogenic factor)]
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1.
Two forms " , ß only 20% homology but bind to same receptors
2.
No signal peptide - initially produced an inactive pro-IL-1, which is
intracellular; cleaved by ICE (apoptosis enzyme – caspase 1); mechanism
of secretion unknown. ??Membrane IL-1.
3.
Produced by many cell types - macrophages, epithelial cells, dendritic
B/T, astrocytes - major producer in the macrophages
4.
Stimulus - irritant (UV light), T-M N interaction, other cytokines - TNF
5.
Activities - involved in fever induction, acute phase response in liver,
many immunological functions are analogous to TNF; initially discovered
as being involved in T cell activation; ? induce production of high affinity
IL-2 receptors
B.
Tumor Necrosis Factor [(TNF α , ß); Lymphotoxin (TNFß)]
1.
Two forms α , ß - 30% homology - bind to same receptors
2.
Long signal peptide segment (TNF α ) for M N released; TNFß is released
from activated T (esp. Tc) cells. Same question as IL-1 for mechanism of
TNF α release but membrane form as a type II protein is confirmed. Is
trimeric.
3.
Now obvious that a large family of cell-cell interaction molecules are
homologous with TNF and the receptors are also related: CD40/CD40L;
Fas/FasL; others with yet unknown function.
4.
TNF α - produced mainly by monocytes/macrophages some production by
lymphocytes. TNFß produced by T cells, may be in granules; released
along with granule contents
5.
Stimulus - for M N - same as IL-1. For T cells activation of Tc causes
TNFß release.
6.
Activities - Regression of some tumors - led to name TNF; other name is
cachexia "I have it bad" - wasting syndrome, septic shock, (Schwartzman
Reaction). Inflammation/granuloma formation.
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III.
IL-6 [B cell growth/differentiation factor, hepatocyte GF]
1.
. 20 Kd glycoprotein
2.
Produced by monocytes, T cells, fibroblasts, endothelial cells
3.
Function - promotes Ig production and B cell differentiation, promotes
continues growth/survival of plasma cells - (transgenics with elevated IL-6
die of myeloma) supports T cell growth along with IL-1 - Induces acute
phase proteins from hepatocytes
4.
IL-11 shares many of IL-6 functions, including critical receptor
"triggering" chain (gp130)
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B.
IL-8 [NAP-1] MDNCF member of α-chemokine-family
1.
One of a growing number (20 + ) of low mw "acute phase" proteins. IL-8 is
a 72 amino acid peptide/8 Kd mw that exists as a dimer. Charac. of " " "
family is that first two of four cys have a single a.a. interspersed, i.e.,
CXC.
2.
Produced by monocytes/macrophages, fibroblasts epithelial cells
3.
Stimulus - TNF/IL-1
4.
Function - chemotaxis of PMN, and (to a lesser degree) T cells, basophils.
Activation of PMN.
5.
Chemokine- family is related low mw, usually dimeric, first two of the
four cys have no interspersed a.a., i.e. CC. Prototypic example is MIP- "
a. Primarily chemotactic for monocytes/macrophages
b. Implicated recently as “suppressive agent for HIV”
A.
Type I interferon
1.
Two forms; Interferon " (leukocyte-IFN) and ß (fibroblast-IFN), forms
show little homology but bind to same receptors. IFN- γ is a further
division of IFN-γ.
3
Most potent signal for type I IFN induction is viral infection and is
experimentally induced with double stranded RNA
4.
Biologic activities
a.
b.
Inhibits viral replication--paracrine like manner
c.
Increases lytic potential of NK cells
d.
Modulates (increases) MHC class I expression
2.
18-20 Kd proteins made by a variety of cells esp in response to viral inf.
Inhibits cell proliferation
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