Cytokines
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Transcript of Cytokines
Cytokines
Lu Qing, PhD , MDDepartment of Immunology
School of Medicin, Fudan UniversityTel : 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 sourcesmonokines (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
General PropertiesFunctional Categories of CytokinesCytokine ReceptorsBiologic Actions
Cytokines
General PropertiesFunctional Categories of CytokinesCytokine ReceptorsBiologic 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
Bacterium becomes attached to membrane evaginations called pseudopodia
Bacterium is ingested, forming phagosome
Phagosome fuses with lysosome
Lysosomal enzymes digest captured material
Digestion products are released from cell
(a)
(b)
NK cells-kill infected cells and tumor cells
perforin/granzyme (cytolysis) Fas/FasLTNF-/TNFR-I
Cell apoptosis
NK cells secret cytokine, mainly IFN-—to activate macrophage to destroy phagocytosed microbes.
Tumor necrosis factor (TNF) IL-1 IL-12Type I IFNs IL-15 IL-18
Mononuclear phagocytes are the principal source of cytokines of innate immunity
As a result of cellular activation:
Innate and adaptive Immunity
Repertoire of clones
Recognition of processed antigens:
peptide-MHC
ResponseClonal expansion
Functional differentiationMemory
Tolerance to self
Activation phaseTH1 ( IFN- )TH2 ( IL-4,5, 13 ) TH17 ( IL-17 ) TR1 ( IL-10 ) Foxp3+Treg
CTL
Three elemental R‘s of T-cell biology: repertoire, recognition, response
Effector phase
Recognition phase
Cytokine production is one of the principal response of T cells to antigen recognition
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
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
What are cytokines?
Cytokine actions may be local and systemic
Autocrineaction
Endocrine action
circulation
act at a distance from the site of infection
Paracrine action act on a nearby cell
act on cytokine-producing cell itself
T lymphocytes often secret cytokines at the site of contact with antigen-presenting cells .
Most cytokines act close to where they are produced
pleiotropismredundancysynergyantagonism
Cytokines
General PropertiesFunctional Categories of CytokinesCytokine ReceptorsBiologic Actions
Functional Categories of Cytokines
Mediators and regulators of innate immunityTumor necrosis factor (TNF), IL-1, IL-6, IL-12, Type I IFNs, IL-15, IL-18,chemokines
Mediators and regulators of adptive immunityIL-2, IL-4, IL-5, IFN-g, TGF-, LT(TNF- ), IL-13,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 PropertiesFunctional Categories of CytokinesCytokine ReceptorsBiologic Actions
Cytokine Receptors
Type I cytokine receptorsType II cytokine receptors Ig superfamilyTNF receptorsSeven-transmembrane -helical receptors
*Classification of cytokine receptors based on structural homologies among the extracellular cytokine-binding domain.
-S-
S-
-S-
S-
-S-
S-
CC
C C
C1C3C2
C1C3C2
C1C3C2
C1C3C2
G protein
Ig superfamily
Type I cytokine-R
Type II cytokine-R
TNF-R Chemokine-R
IL-1 M-CSF C-kit
IL-2 IL-3 IL-4 IL-5 IL-6 IL-7
IL-9 IL-11 IL-12 IL-13 IL-15 OSM
GM-CSF
G-CSF EPO
IFN- IFN- IFN-IL-10
TNF- TNF- CD40L NGF FASL
IL-8 RANTES MIP-1 PF4
Cytokine receptor families and ligands
WSXWS
Conserved cycteins
–chain shared by IL-2 receptor family
IL-2R IL-4R IL-7R IL-9R IL-15R
common 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 PropertiesFunctional Categories of CytokinesCytokine ReceptorsBiologic 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
*Mononuclear phagocytes are the principal source of cytokines of innate immunity
Tumor necrosis factor (TNF) IL-1 IL-6chemokinesType I IFNs IL-12 IL-15 IL-18
Proinflammatory cytokines
Cytokines That Mediate and Regulate Innate Immunity
Active recruitment of the cells to the sites of infectionrecognition of microbes phagocytosis destruction
TNF
Low quantities(plasma conc.<10-9M)
Moderate quantities
High quantities(plasma conc.10-
7M)
Local inflammationSystemic effects Septic shock
Leukocyte
Activation
Adhesion molecule
Endothelial cell
IL-1,chemokines
FeverLow output
Hypoglycemia
Thrombus
*Mononuclear phagocytes are the principal source of cytokines of innate immunity
Tumor necrosis factor (TNF) IL-1 IL-6chemokines IL-12Type I IFNs IL-15 IL-18
Cytokines That Mediate and Regulate Innate Immunity
inflammation
BloodSecondary
lymphoid organs
Primary lymphoid organs
Tissue
directing migration of leukocytesChemokines
Physiologic traffic of lymphocytes through the organs
(1) inflammatory stimuli
(2) Constitutively produced in lymphoid organs
to inflammatory sites
Cellular sourcesCellular sources
Chemokine family and structure
The chemokines are classified into families based on the number and locationnumber and location of N-terminal of cyctein residues CXC 、 CC 、 C 、 CX3C
C: cycteinX: any amino acid
Family Structure
leukocytesendothelial cells epithelial cells fibroblasts
CXCL8/IL-8
CXCL4/PF4
CXCL1/GROα
CXCL10/IP-10
lymphocytes
Endothelial cells
neutrophils
CXC chemokines Microbesinflammatory
cytokines CCL2/MCP-1
CCL3/MIP-1
CCL5/RANTES
CCL11/Eotaxin
eosinophils
Mononuclear phagocytes
CC chemokines
basophilslymphocytes
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 antibodie
s, complement components, etc.)• Sticky for leukocytes, leading to influx of neutrophils
first, then monocytes, lymphocytesChemokines induce movement of leukocytes and their
migration toward chemical gradient of the cytokine
inflammation
BloodSecondary
lymphoid organs
Primary lymphoid organs
Tissue
directing migration of leukocytesChemokines
Physiologic traffic of lymphocytes through the organs
(1) inflammatory stimuli
(2) Constitutively produced in lymphoid organs
to inflammatory sites
Segregation of B cells and T cells in distinct areas of the lymph node is dependent on cytokines.
Chemokines regulate the traffic of lymphocytes and other cells through peripheral lymphoid tissues
CXCR5/CCR7
*Mononuclear phagocytes are the principal source of cytokines of innate immunity
Tumor necrosis factor (TNF) IL-1 IL-6chemokinesType I IFNs IL-12 IL-15 IL-18
Cytokines That Mediate and Regulate Innate Immunity
Type I IFNs
Major cellular sourcesIFN-: mononuclear phagocytes IFN-: fibroblasts
Potent stimulusviral infection
Functionmediate 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
virus
Viral replication
Induction of “antiviral state”
IFN-
Induction of enzymes that block viral replication
Potent stimulus
nucleus nucleus
Virus infected cells Nearby uninfected cell
*Mononuclear phagocytes are the principal source of cytokines of innate immunity
Tumor necrosis factor (TNF) IL-1 IL-6chemokinesType I IFNs IL-12 IL-15 IL-18
Cytokines That Mediate and Regulate Innate Immunity
Macrophage
Microbes
Activation
Dendriticcell
Antigen presentation
CD40 CD40LNaïve CD4+T cell
IL-12
TH1 cell
NK cell
IFN-
Macrophage activation;killing of phagocytosed microbes
CD8+ T cell
Killing of infected cell
Increased cytolytic activity
NK cell
Roles of cytokines in innate immunity and inflammation
0 1 3 6
Hours after LPS injection
Biologic Actions
Cytokines That Mediate and Regulate Innate Immunity
Cytokines That Mediate and Regulate Adaptive Immunity
Cytokines That Stimulate Hematopoiesis
Repertoire of clones
Recognition of processed antigens:
peptide-MHC
ResponseClonal expansion
Functional differentiationMemory
Tolerance to self
Activation phaseTH1 ( IFN- )TH2 ( IL-4,5, 13 ) TH17 ( IL-17 ) TR1 ( IL-10 ) Foxp3+Treg
CTL
Three elemental R‘s of T-cell biology: repertoire, recognition, response
Effector phase
Recognition phase
Cytokine production is one of the principal response of T cells to 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
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
Leukocyte recruitment (inflammation)
Neutrophil activation (killing of phagocytosed microbes)
IFN-: A principal macrophage-activating cytokine
IFN- 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
• 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, leukocytesFunction: stimulate the growth and differentiation of immature leukocytesMembers: granulocyte-CSF, G-CSF macrophage-CSF , M - CSF granulocyte-macrophage-CSF, GM-CSF) erythropoietin, EPO TPO stem cell factor, SCF
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