Download CYTOKINES AND CHEMOKINES March 27, 2008 Ronald B. Smeltz

M1 – Immunology
CYTOKINES AND CHEMOKINES
March 26, 2009
Ronald B. Smeltz, Ph.D.
[email protected]
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Learning Objectives
1. Define the term cytokine
2. Recognize and understand the difference between a cytokine and
chemokine
3. Discuss the mode-of-action for cytokines
4. Know the functions of TGF-, TNF, and IFN-
5. Contrast the roles of IL-12 and IL-10 in inflammation
6. Predict the consequence of mutations in the common c receptor
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I.
Cytokines and cytokine receptors:
Basic concepts
A.
Definitions:
1.
A cytokine is a protein made by a cell, that when it binds to a
cytokine receptor it exerts a biological effect.
–
Example: IFN- (gamma interferon)
•
Cytokines cause naïve T cells to differentiate into effector cells
with specialized effector functions (Th1, Th2, Th17, Treg)
•
A lymphokine is a cytokine produced by a lymphocyte. An
interleukin (IL) is a generic term used for many lymphokines:
IL-2
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I.
Cytokines and cytokine receptors:
Basic concepts
2. A chemokine is a special type of cytokine, known as a
chemoattractant cytokine
CXCL8: recruits neutrophils from blood into tissues
Most cytokines are beneficial and act locally
However, cytokines can also have negative effects on the host:
• dysregulated cytokine production can cause tissue damage
• systemic cytokine production can cause death
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I.
Cytokines and cytokine receptors:
Basic concepts
B. How do cytokines work?
• Secretion
• Binding to cytokine receptor
• Activation of Jak-Stat pathway
• Biological effect
1. Cytokines can be secreted in the following manner:
• autocrine production: when the cell that secretes the cytokine is
also the target cell
• paracrine production: when the cytokine binds to a receptor that
is expressed on a neighboring cell
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Autocrine production
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Paracrine production
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I.
Cytokines and cytokine receptors:
Basic concepts
2. Cytokines bind to receptors with different structures:
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I.
Cytokines and cytokine receptors:
Basic concepts
3. After a cytokine binds to a cytokine receptor, the JAK-STAT
pathway is activated and leads to increased transcription of genes.
STAT: Signal Transducers and Activators of Transcription
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II. Categories of cytokines important for
the immune system
A. COMMON GAMMA CHAIN CYTOKINES (c)
• IL-2 , IL-7, IL-15
Cytokine
Biological effects
IL-2
T cell growth
IL-7
T cell survival
IL-15
T cell survival, memory T cells
NK cell development
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II. Categories of cytokines important for
the immune system
Common gamma chain (c) cytokine receptor
 All common gamma chain cytokines use the common c
receptor
 X-linked severe combined immunodeficiency
syndrome(X-SCID)
1. mutation in c
2. severe deficiency in T cells and NK cells, defective
B cell responses (B cells cannot class switch
properly)
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II. Categories of cytokines important for
the immune system
B. PRO-INFLAMMATORY CYTOKINES:
IL-12 family, interferons, TNF family
1. IL-12 family
 IL-12, IL-23, IL-27
 Products of macrophages and dendritic cells
 Effects of IL-12:
1. Stimulates secretion of IFN-
2. Induces the differentiation of T cells into IFN-producing Th1 cells
3. Immunity to intracellular pathogens (M.
tuberculosis)
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II. Categories of cytokines important for
the immune system
IL-12 receptor:
 Patients with IL-12 or IL-12R1 deficiencies are highly
susceptible to Salmonella and Mycobacterial infections
 How could a mutation in a cytokine receptor be more
severe than a mutation in the cytokine that binds to that
receptor?
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II. Categories of cytokines important for
the immune system
2.
Interferons
•
IFN-, IFN-, IFN-
Originally called interferons because they interfered with viral
replication. Double-stranded RNA is a potent inducer of IFN. There are two types of interferons:
a. Type I interferons:
•
•
IFN-: produced by leukocytes, dendritic cells
IFN-: produced by fibroblasts
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Effects of Type I interferons
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II. Categories of cytokines important for
the immune system
b. Type II interferons


IFN- (gamma interferon)
Produced by Th1 cells and NK cells

Effects of IFN-:
a. activates macrophages
b. increased killing of intracellular pathogens
c. increased expression of MHC molecules
d. increased antigen presentation
e. promotes antibody class switching
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II. Categories of cytokines important for
the immune system
•
Hereditary IFN-R-deficiency
–
severe infections, death from intracellular bacterial infections
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II. Categories of cytokines important for
the immune system
3. Tumor Necrosis Factor (TNF) family
 TNF-, TNF- (lymphotoxin ), lymphotoxin , Fas-L,
CD40 ligand
Cytokine
Biological effects
TNF-
Activates neutrophils,
macrophages
TNF- (lymphotoxin-)
Cytotoxicity
lymphotoxin-
Lymph node development
Fas-L
Apoptosis
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II. Categories of cytokines important for
the immune system
Effects of TNF- production:
Local TNF-
• stimulates IL-12 production, IL-12 induces IFN- production,
IFN- activates macrophages, stimulates further TNF-
production, containment of infection
Excessive local TNF-
• autoimmune disease (rheumatoid arthritis)
Systemic TNF-
• septic shock
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II. Categories of cytokines important for
the immune system
TNF receptor:
Mutations in Fas can cause defects in apoptosis (ie. ALPS)
Mutations in CD40L can lead to hyper IgM syndrome. Why?
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II. Categories of cytokines important for
the immune system
C. ANTI-INFLAMMATORY CYTOKINES

Transforming growth factor  (TGF-, IL-10

Effects of TGF-
1. Inhibits T cell proliferation
2. Inhibits inflammation
3. Regulatory T cells (Treg) can express TGF-

Effects of IL-10:
1. Suppresses IL-12 production by macrophages
2. Inhibits T cell proliferation
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III. Chemokine and chemokine receptors
• Chemokines are chemoattractant cytokines. They
are chemoattractant because they act as chemical
signals to attract and recruit leukocytes from the
blood into various tissues and organs.
How to recognize a chemokine
“L” = chemokine ligand
i. CXCL would be a chemokine
“R” = chemokine receptor
i. CXCR would be a chemokine receptor
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III. Chemokine and chemokine receptors
• Chemokine receptors are a class of 7-transmembrane, Gprotein-coupled receptors
How do cytokine and chemokine receptors differ?
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III. Chemokine and chemokine receptors
Important functions of chemokines:
1. Recruitment of lymphocytes into lymphoid tissues
2. Recruitment of cells from bone marrow to combat infection
3. Recruitment of cells into inflammatory sites
Chemokines are selective for the cells they recruit:
1. CXCL8:
2. CCL2:
3. CCL11
4. CXCL13:
5. XCL1:
neutrophils
monocytes
eosinophils
B cells
T cells
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IV. Chemokines and chemokine receptors
of clinical relevance
1. CXCL4
• CXCL4-heparin complexes
• cause autoimmune heparin-induced thrombocytopenia
2. CXCR4 and CCR5
• HIV uses these receptors to infect cells
3. DARC (Duffy antigen receptor for chemokines)
• Plasmodium (causative agent of malaria) uses DARC to infect cells
4. CXCL8
• glomerulonephritis
5. CCL2 and CCL5
• Recruit macrophages into atherosclerotic plaques
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