cytokines non-antibody proteins acting as mediators between cells, termed: monokines – mononuclear...
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Cytokines
Non-antibody proteins acting as mediators between cells, termed:
• Monokines – mononuclear phagocytes• Lymphokines – activated T cells, especially
helper T cells• Interleukins – abbreviated IL with a number
Properties of Cytokines1. Produced by cells involved in both natural
and specific immunity
2. Mediate and regulate immune responses
3. Secretion brief and limited - not stored pre-formed - synthesis initiated by gene transcription - mRNA short-lived - cytokines produced as needed
Properties of Cytokines(continued)
4. Can be produced by many cell types and act on many cell types (pleiotropic)
5. Can have similar actions (redundant)
IL2
Rα
IL2
Rβ
IL2
Rγ
IL15
Rα
IL2
Rβ
IL2
Rγ
IL7
R
IL2
Rγ
?
IL9
R
IL2
Rγ
IL4
R
IL2
Rγ
IL-2 IL-15 IL-7 IL-9 IL-4Receptor for:
Properties of Cytokines (continued)
6. Can influence synthesis of other cytokines - produce cascades - enhance or suppress production of other
cytokines - exert positive or negative regulatory mechanisms
for immune responses7. Influence action of other cytokines - can be antagonistic, additive, synergistic
Properties of Cytokines (continued)
8. Bind to receptors with high affinity
9. Cells responding to cytokine can be:
- same cell (autocrine)
- nearby cell (paracrine)
- distant cell by circulation (endocrine)
10. Cellular responses to cytokines are slow, require new mRNA and protein synthesis
• Tumor Necrosis Factor-alpha (TNF-α)
• Interleukin-1 (IL-1)
• Chemokines (Chemotactic cytokines)
• Type I Interferons (IFN-α and IFN-β)
• Interleukin-12 (IL-12)
• Interleukin-10 (IL-10)
Mediators and Regulators of Natural Immunity
Tumor Necrosis Factor (TNF-α)
• Produced by activated macrophages• Most important mediator of acute inflammation in
response to microbes, especially Gram-negative bacteria (LPS)
• Mediates recruitment of neutrophils and macrophages to site of inflammation
• Acts on hypothalamus to produce fever• Promotes production of acute phase proteins
Interleukin-1 (IL-1)
• Produced by activated macrophages
• Effects similar to those of TNF-α
Chemokines
• Produced by many different leukocytes and tissue cells
• Large family of >50 substances
• Recruit leukocytes to sites of infection
• Play a role in lymphocyte trafficking
Type I Interferons (IFN-α and β)
• IFN-α a family of many proteins produced by macrophages, IFN-β a single protein produced by many cells
• Both IFNs inhibit viral replication• Both increase expression of class I MHC• Both activate NK cells
Interleukin-12 (IL-12)• Produced by activated macrophages and
dendritic cells
• Stimulates production of IFN-γ
• Induces differentiation of Th cells to become Th1 cells
• Enhances cytolytic functions of cytotoxic T cells and NK cells
Interleukin-10 (IL-10)• Produced by activated macrophages,
Th2 cells• An inhibitory cytokine• Inhibits cytokine production by
activated macrophages• Inhibits expression of class II MHC
and costimulatory molecules on macrophages
Mediators and Regulators of Specific Immunity
• Interleukin-2 (IL-2)
• Interleukin-4 (IL-4)
• Interleukin-5 (IL-5)
• Interleukin-10 (IL-10)
• Interferon-gamma (IFN-γ)
Interleukin-2 (IL-2)• Produced by Th>>Tc
• Main growth factor for T cells
IL-2secretion
T cell
NKIncrease in NK
Cell activity
B cell Stimulationof division
T cell
Stimulation of division and IFN gamma
release (and other mediators)
MonocyteMonocyte
Activation
Autocrine Function of IL-2
ActivatedT cell
RestingT cell
Class II MHCAPC
T cell
T cell T cell T cell T cell
T cell T cell T cell T cell
IL2 IL4 IL7
Binds to IL-2 receptor
Receptordecay
Division
Interleukin-4 (IL-4)
• Produced by Th2 cells• Stimulates Ig class switching to IgE
isotype• Stimulates development of Th2 cells
from naïve Th cells• Promotes growth of differentiated Th2
cells
Interleukin-5 (IL-5)
• Produced by Th2 cells• Promotes growth and differentiation of
eosinophils• Activates mature eosinophils• IL-4 and IL-5 can work together Helminths
opsonized with IgE can be killed by activated eosinophils
Interleukin-10 (IL-10)
• Produced by activated macrophages, Th2 cells
• Inhibits production of IFN-γ by Th1 cells needed to activate macrophages
Interferon-gamma (IFN-γ)• Produced by Th cells >> Tc and NK cells
• Numerous functions in both natural and specific immunity
Bcell
MacrophageMacrophageNK
T cell
Th1 cell > Tc cell
NK
Many cell types Many cell types
Induction of class I and class II MHC
Increase in NK
cell activity
Differentiation,Stops cell divisionT cell activation
Weak anti-viral activity,Stops cell division,
Stops hematopoiesis
Activation
GranulocyteGranulocyte
Activation
Endothelial cellActivation
IFN gammasecretion
Stimulators of Hematopoiesis
• Granulocyte-macrophage CSF (GM-CSF) promotes growth and differentiation of bone marrow progenitors
• Macrophage CSF (M-CSF) is involved in development and function of monocytes and macrophages
• Granulocyte CSF (G-CSF) stimulates production of polymorphonuclear leucocytes (PMN)
Colony-Stimulating Factors (CSF)
Cytokines Regulate Ig Class Switching
• Fc region of antibodies determines effector function in different anatomical locations
• Class (isotype) switching produces class or subclass of antibody most effective in host defense
• Cytokines acting alone or in combination regulate class switching
Cytokine Network
• Many cytokines have effects on many cells and organ systems in addition to functions in immune systems
• Referred to as the “cytokine network”
Effects on Cells of Immune System
LymphocyteMacrophageMacrophage
Bcell T cell NK LAK
Proliferation,Differentiation,
Ig secretion and selection
Proliferation,Differentiation,
Cytokineproduction
Activation of cells of immune system Cytokine production
IL1 IL2 IL4
IL1 IL2 IL4 IL5 IL6 IFNγ
cytokines
Cytokine Effects on Organ Systems
Lymphocyte MacrophageMacrophage
Hypothalmus
ACTH
Adrenalgland
Corticosteroid
Liver
Acute phase proteins
Pituitary
IL1 IL6 TNFIL1 IL6 TNF
Fever
-cortisol +
DHEA
IL 6
cytokines
Cytokine Effects on Various Cells
Lymphocyte MacrophageMacrophage
FibrogenesisExtracellular
matrix
cytokines
IL1 TNF
Endothelial cell
Fibroblasts
FibrinogenPermeability change
adhesion
Endothelial cells
cytokines
TNF IL1 IF
Nγ
Hematopoiesis
Bone marrow
IL3 CSFs
cytokines
AngiogenesisFibroblast
Extracellular matrix
Osteoclasts
Tissue remodeling
Tissue repair
IL1
TNF
Anti-viralstate
Many cell types
IL1 TNF IFNα IFNβ IFNγ