Transcript Cytokines That Mediate and Regulate Innate Immunity inflammation

Cytokines
Lu Qing, PhD，MD
Department of Immunology
School of Medicin, Fudan University
Tel：5423-7093
E-mail: [email protected]
What are cytokines?
 “Cytokines” are soluble protein secreted by the
cells of innate and adaptive immunity and
therefore mediate many of the functions of these
cells
 Based on their cellular sources
monokines (mononuclear phagocyte)
lymphokines (lymphocytes)
interlukins (leukocytes) (IL-1, IL-2, etc.)
 A subfamily of cytokines primarily functions in
directing migration of cells, these are called
“chemotactic cytokines” or “chemokines”
Cytokines
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General Properties
Functional Categories of Cytokines
Cytokine Receptors
Biologic Actions
Cytokines
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General Properties
Functional Categories of Cytokines
Cytokine Receptors
Biologic Actions
Innate and adaptive Immunity
Phagocytes-identify, ingest, and destroy microbes
Mononuclear phagocytes
Neutrophils (polymorphonuclear
leukocytes)
Short-lived (6h);
the most abundant population
of circulating WBCs;
mediate the earliest phase of
inflammatory response
(b)
Bacterium becomes attached to membrane
evaginations called pseudopodia
Bacterium is ingested, forming phagosome
Phagosome fuses with lysosome
Lysosomal enzymes digest captured material
(a)
Digestion products are released from cell
NK cells-kill infected cells and tumor cells
 perforin/granzyme (cytolysis)
 Fas/FasL
Cell apoptosis
 TNF-/TNFR-I
As a result of cellular activation:
Mononuclear phagocytes are the principal source of
cytokines of innate immunity
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Tumor necrosis factor (TNF)
IL-1
IL-12
Type I IFNs
IL-15
IL-18
NK cells secret cytokine, mainly IFN-g—to activate
macrophage to destroy phagocytosed microbes.
Innate and adaptive Immunity
Three elemental R‘s of T-cell biology:
repertoire, recognition, response
Repertoire of clones
Recognition phase
Recognition of
processed antigens:
peptide-MHC
Cytokine production is one of the principal
response of T cells to antigen recognition
Activation phase
Response
Clonal expansion
Functional differentiation
Memory
Tolerance to self
Effector phase
TH1（IFN-g）
TH2（IL-4,5, 13）
TH17（IL-17）
TR1（IL-10）
Foxp3+Treg
CTL
T lymphocytes in response to Ags are the
principal sources of cytokine in adaptive
immunity .
The function of T helper cells is mediated by
cytokines
What are cytokines?
 Cytokines are polypeptides
produced by the cells of innate
and adaptive immunity in
response to microbes and other
antigens as a result of cellular
activation.
 Cytokines initiate their actions
by binding to specific membrane
receptors on target cells.
The cellular responses to most
cytokines consist of gene
activation, resulting in the
expression of new functions and
sometimes the proliferation of
the target cells
Cytokine actions may be local and systemic
Autocrine
action
act on cytokine-producing cell itself
Paracrine action
act on a nearby cell
circulation
Endocrine action
act at a distance from the site of infection
Most cytokines act close to where they are produced
 T lymphocytes often secret cytokines at the site
of contact with antigen-presenting cells .
pleiotropism
redundancy
synergy
antagonism
Cytokines
 General Properties
 Functional Categories of Cytokines
 Cytokine Receptors
 Biologic Actions
Functional Categories of Cytokines
 Mediators and regulators of innate immunity
Tumor necrosis factor (TNF), IL-1, IL-6, IL-12,
Type I IFNs, IL-15, IL-18,chemokines
 Mediators and regulators of adptive immunity
IL-2, IL-4, IL-5, IFN-g, TGF-, LT(TNF- ), IL13,etc
 Stimulators of hematopoiesis
granulocyte-CSF, G-CSF
macrophage-CSF，M－CSF
granulocyte-macrophage-CSF, GM-CSF)
erythropoietin, EPO
TPO
stem cell factor, SCF
Cytokines
 General Properties
 Functional Categories of Cytokines
 Cytokine Receptors
 Biologic Actions
Cytokine Receptors
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Type I cytokine receptors
Type II cytokine receptors
Ig superfamily
TNF receptors
Seven-transmembrane -helical receptors
*Classification of cytokine receptors based on
structural homologies among the extracellular
cytokine-binding domain.
Cytokine receptor families and ligands
Ig
superfamily
Type I
cytokine-R
Type II
cytokine-R
TNF-R
Chemokine-R
-S-S-
C1
C3
C2
-S-S-
C1
C3
C2
-S-S-
Conserved
cycteins
WSXWS
C
C
C1
C3
C2
C
C1
C3
C2
C
G protein
IL-1 MCSF Ckit
IL-2
IL-3
IL-4
IL-5
IL-6
IL-7
IL-9 GM-CSF
IL-11 G-CSF
IL-12 EPO
IL-13
IL-15
OSM
IFN-
IFN-
IFN-g
IL-10
TNF-
TNF-
CD40L
NGF
FASL
IL-8
RANTES
MIP-1
PF4
g –chain shared by IL-2 receptor family
IL-2R
IL-4R

 g
 g
IL-7R
IL-9R
IL-15R

 g
common g chain
Cytokine receptors consist of unique ligand-binding chains and
one or more signal-transducing chains,which are often shared
by receptors for different cytokines
Cytokine receptors and signaling
Different cytokines binding to cytokine receptors
activated distinct signal transduction pathways
resulting in gene activation.
Cytokines
 General Properties
 Functional Categories of Cytokines
 Cytokine Receptors
 Biologic Actions
Biologic Actions
 Cytokines That Mediate and Regulate Innate
Immunity
 Cytokines That Mediate and Regulate Adaptive
Immunity
 Cytokines That Stimulate Hematopoiesis
*Cytokines have many functions, we’ll focus on a
few central functions of a few key cytokines
Cytokines
That Mediate and Regulate Innate Immunity
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Tumor necrosis factor (TNF)
IL-1
IL-6
chemokines
Type I IFNs
IL-12
IL-15
IL-18
Proinflammatory
cytokines
*Mononuclear phagocytes are the principal source of
cytokines of innate immunity
Active recruitment of the cells to the sites of
infection
recognition of microbes phagocytosis destruction
TNF
Low quantities
(plasma conc.<10-9M)
Moderate
quantities
High quantities
(plasma conc.10-7M)
Systemic effects
Septic shock
Local inflammation
Leukocyte
Fever
Low output
Activation
Adhesion
molecule
Thrombus
IL-1,
chemokines
Endothelial cell
Hypoglycemia
Cytokines
That Mediate and Regulate Innate Immunity
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Tumor necrosis factor (TNF)
IL-1
IL-6
chemokines
IL-12
Type I IFNs
IL-15
IL-18
*Mononuclear phagocytes are the principal source of
cytokines of innate immunity
Chemokines
Primary
lymphoid
organs
Secondary
lymphoid
organs
directing migration of leukocytes
Blood
Tissue
inflammation
Cellular sources
(1) inflammatory stimuli
to inflammatory
sites
(2) Constitutively produced in lymphoid
organs
Physiologic
traffic of lymphocytes through the organs
Chemokine family and structure
Family
Structure
X: any amino acid
C: cyctein
The chemokines are classified into families based
on the number and location of N-terminal of
cyctein residues
CXC、CC、C、CX3C
CXC chemokines
Microbes
inflammatory cytokines
CXCL8/IL-8
CXCL1/GROα
CXCL4/PF4
leukocytes
endothelial cells
epithelial cells
fibroblasts
CC chemokines
CCL2/MCP-1
CCL3/MIP-1
CCL5/RANTES
CCL11/Eotaxin
CXCL10/IP-10
neutrophils
lymphocytes
Endothelial cells
lymphocytes
basophils
eosinophils
Mononuclear phagocytes
The chemokine/chemokine-receptor family
Chemokines recruit the cells to sites of infection
Cytokines and Inflammation
 Macrophages or DCs stimulated via microbes make
pro-inflammatory cytokines, especially TNF (Tumor
necrosis factor), IL-1, and IL-6
 TNF and IL-1 signal to endothelial cells to make
them:
• Leaky to fluid (influx of plasma; containing
antibodies, complement components, etc.)
• Sticky for leukocytes, leading to influx of
neutrophils first, then monocytes, lymphocytes
 Chemokines induce movement of leukocytes and their
migration toward chemical gradient of the cytokine
Chemokines
Primary
lymphoid
organs
Secondary
lymphoid
organs
directing migration of leukocytes
Blood
Tissue
inflammation
(1) inflammatory stimuli
to inflammatory
sites
(2) Constitutively produced in lymphoid
organs
Physiologic traffic of lymphocytes through the
organs
Chemokines regulate the traffic of lymphocytes and
other cells through peripheral lymphoid tissues
CXCR5/CCR7
Segregation of B cells and T cells in distinct areas of the lymph
node is dependent on cytokines.
Cytokines
That Mediate and Regulate Innate Immunity








Tumor necrosis factor (TNF)
IL-1
IL-6
chemokines
Type I IFNs
IL-12
IL-15
IL-18
*Mononuclear phagocytes are the principal source of
cytokines of innate immunity
Type I IFNs
 Major cellular sources
IFN-: mononuclear phagocytes
IFN-: fibroblasts
 Potent stimulus
viral infection
 Function
mediate the early innate immune response to viral
infections
Inhibits viral replication
Increase expression of class I MHC molecules
Stimulates the development of Th1 cells in human
type I IFN inhibits viral replication
Induction of
“antiviral state”
virus
Viral replication
Induction of enzymes that
block viral replication
Potent
stimulus
nucleus
Virus infected cells
nucleus
IFN-
Nearby uninfected cell
Cytokines
That Mediate and Regulate Innate Immunity








Tumor necrosis factor (TNF)
IL-1
IL-6
chemokines
Type I IFNs
IL-12
IL-15
IL-18
*Mononuclear phagocytes are the principal source of
cytokines of innate immunity
Microbes
Antigen
presentation
Activation
Macrophage
Naïve
CD4+
T cell
Dendritic
cell
CD40 CD40L
IL-12
CD8+ T cell
NK
cell
TH1
cell
IFN-g
Macrophage activation;
killing of phagocytosed microbes
NK
cell
Increased cytolytic activity
Killing of infected cell
Roles of cytokines in innate immunity and inflammation
0
1
3
Hours after LPS injection
6
Biologic Actions
 Cytokines That Mediate and Regulate Innate
Immunity
 Cytokines That Mediate and Regulate Adaptive
Immunity
 Cytokines That Stimulate Hematopoiesis
Three elemental R‘s of T-cell biology:
repertoire, recognition, response
Repertoire of clones
Recognition phase
Recognition of
processed antigens:
peptide-MHC
Cytokine production is one of the principal
response of T cells to antigen recognition
Activation phase
Response
Clonal expansion
Functional differentiation
Memory
Tolerance to self
Effector phase
TH1（IFN-g）
TH2（IL-4,5, 13）
TH17（IL-17）
TR1（IL-10）
Foxp3+Treg
CTL
Function of T cell derived Cytokines
 In the activation phase of T cell-dependant immune
response:
Regulate the growth and differentiation of various
lymphocyte population
 In the effector phase of adaptive immune response:
Recruit, activate, and regulate specialized
effector cells, such as mononuclear phagocytes,
neutrophils, and eosinophils, to eliminate antigens
 Cytokine of adaptive immunity are produced mainly by T
lymphocytes in response to specific recognition of protein Ags.
The function of T helper cells is mediated by cytokines
Figure 8-20
IL-2
• a growth factor for antigen-stimulated T
lymphocytes
• responsible for T cell clonal expansion
after antigen recognition
Function of T cell derived Cytokines
 In the activation phase of T cell-dependant immune
response:
Regulate the growth and differentiation of various
lymphocyte population
 In the effector phase of adaptive immune response:
Recruit, activate, and regulate specialized
effector cells, such as mononuclear phagocytes,
neutrophils, and eosinophils, to eliminate antigens
IFN-g: A principal macrophage-activating cytokine
Leukocyte recruitment (inflammation)
Neutrophil activation (killing of phagocytosed microbes)
 IFN-g treatment inhibits the propagation of
Leishmania that survive within macrophages
• A more detailed introduction of functions
of cytokines in adaptive immune response
are in charpter 13 (Effector Mechanisms of
Cell-Mediated Immunity)
Biologic Actions
 Cytokines That Mediate and Regulate Innate
Immunity
 Cytokines That Mediate and Regulate Adaptive
Immunity
 Cytokines That Stimulate Hematopoiesis
Pluripotent
stem cells
SCF and IL-7
In summary
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What are cytokines?
Cytokines that mediate innate immunity
Cytokines that mediate adaptive immunity
Cytokines That Stimulate Hematopoiesis
Colony stimulating factor, CSF
Cellular sources:
Bone marrow stromal cells, leukocytes
Function:
stimulate the growth and differentiation of immature
leukocytes
Members:
granulocyte-CSF, G-CSF
macrophage-CSF，M－CSF
granulocyte-macrophage-CSF, GM-CSF)
erythropoietin, EPO
TPO
stem cell factor, SCF
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