Download 07 Cytokines

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 Cytokines
1. 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
- 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 Rγ
IL-4
IL4 R
IL2 Rγ
IL9 R
IL-9
IL2 Rγ
IL7 R
IL-7
?
IL2 Rγ
IL2 Rβ
IL-15
IL15 Rα
IL2 Rγ
IL2 Rβ
IL2 Rα
Receptor for: IL-2
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 responses
7. 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
Mediators and Regulators of
Natural Immunity
•
•
•
•
•
•
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)
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
T cell
B cell
Monocyte
Activation
IL-2
secretion
NK
Stimulation
of division
T cell
Stimulation
of division and IFN gamma
release (and other
Increase in NK
mediators)
Cell activity
Autocrine Function of IL-2
Resting
T cell
Activated
T cell
Class II MHC
APC
IL2
T cell
IL4
Binds to IL-2 receptor
Division
T cell
T cell
T cell
T cell
T cell
T cell
Receptor
decay
T cell
T cell
IL7
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
TH1 cell >
Tc cell
NK
Granulocyte
Endothelial cell
Activation
Activation
IFN gamma
secretion
Macrophage
NK
Activation
Many cell types
Weak anti-viral activity,
Stops cell division,
Stops hematopoiesis
T cell
T cell activation
B
cell
Increase in
NK
cell activity
Many cell types
Differentiation, Induction of class I
Stops cell division and class II MHC
Stimulators of Hematopoiesis
Colony-Stimulating Factors (CSF)
• 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)
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
B
cell
Proliferation,
Differentiation,
Ig secretion
and selection
NK
T cell
Proliferation,
Differentiation,
Cytokine
production
Activation of cells of
immune system
Lymphocyte
cytokines
LAK
Cytokine production
Macrophage
Cytokine Effects on Organ Systems
Hypothalmus
Fever
Pituitary
ACTH
Adrenal
gland
Corticosteroid
Liver
Acute phase proteins
Lymphocyte
cytokines
Macrophage
Cytokine Effects on Various Cells
IL1 TNF IFNα
IFNβ IFNγ
Fibroblasts
Fibrogenesis
Extracellular
matrix
Lymphocyte
cytokines
Macrophage
Many cell types
Anti-viral
state
IL1 TNF
cytokines
Endothelial cell
Endothelial cells
Fibrinogen
Permeability change
adhesion
cytokines
Bone marrow
Hematopoiesis
Tissue
remodeling
Tissue repair
Angiogenesis
Fibroblast
Extracellular
matrix
Osteoclasts
Complement functions
• Host benefit:
–
–
–
–
–
–
opsonization to enhance phagocytosis
phagocyte attraction and activation
lysis of bacteria and infected cells
regulation of antibody responses
clearance of immune complexes
clearance of apoptotic cells
• Host detriment:
– Inflammation, anaphylaxis
Pathways of complement
activation
CLASSICAL
PATHWAY
antibody
dependent
LECTIN
PATHWAY
ALTERNATIVE
PATHWAY
antibody
independent
Activation of C3 and
generation of C5 convertase
activation
of C5
LYTIC ATTACK
PATHWAY
Complement Activation
Bacteria in plasma
Lysis and
ingestion
C1
C2
C4
C1 C2 C4
Complement
activation
Digestion in lysosome
FEATURES OF CYTOKINES
Cytoki
ne
Cell Source
Cell Target
Primary Effects
IL-1
Monocytes
Macrophages
Fibroblasts
Epithelial cells
Endothelial cells
T cells; B cells
Endothelial cells
Hypothalamus
Liver
Costimulatory molecule
Activation (inflammation)
Fever
Acute phase reactants
T cells
B cells
Monocytes
Growth
Growth
Activation
Bone marrow progenitors
Growth and differentiation
Naive T cells
T cells
B cells
Differentiation into a TH 2 cell
Growth
Activation and growth; Isotype switching to
IgE
IL-2
IL-3
T cells; NK cells
T cells
IL-4
T cells
IL-5
T cells
B cells
Eosinophils
Growth and activation
IL-6
T cells; Macrophages;
Fibroblasts
T cells; B cells
Mature B cells
Liver
Costimulatory molecule
Growth (in humans)
Acute phase reactants
IL-8
family
Macrophages; Epithelial
cells; Platelets
Neutrophils
Activation and chemotaxis
IL-10
T cells (TH2)
Macrophages
T cells
Inhibits APC activity
Inhibits cytokine production
IL-12
Macrophages; NK cells
Naive T cells
Differentiation into a TH 1 cell
T cells; NK cells
Monocytes
Endothelial cells
Many tissue cells especially macrophages
Activation
Activation
Increased class I and II MHC
IFNgamm
a