1 CYTOKINES
1.1 INTRODUCTION
regulators of the immune system:
• immune system is located at different sites in the body (primary and secondary lymphoid tissues)
• key to a successful immune system = rapid + effective communication between the cells
1.2 GENERAL PROPERTIES
general properties:
• messenger proteins of the immune system
• mediate the effector functions of the immune system
• provide protection against invading organisms
• regulate the intensity and duration of the response
• other names: monokines, lymphokines, interleukins
• chemokines are cytokines that induce chemotaxis (= directed migration)
• most are soluble proteins
1) released by one cell
2) bind to receptors on another cell
3) induce biological effects
• some are membrane-bound forms (TNF family)
• ligand-receptor interactions of very high affinity ⇒ very potent
• can act in several different ways
o endocrine action
▪ released into bloodstream to affect distant cells
▪ ex. IL-1 ⇒ fever
o paracrine action
▪ released to affect nearby cells
o autocrine action
▪ released
▪ but then bind to receptors on the cell that produced them
• can act in cascades
• the cells of the immune system are subject to control by a network of cytokine interactions
1
,1.2.1 BIOLOGICAL EFFECTS
biological effects:
• induction of proliferation or enhancing survival of target cells
• induction of migration
• changes in differentiation state
• functional classification
o innate immune system
▪ IL-1, TNF-α, CXCL8
▪ secreted by cells of innate immunity (ex. neutrophils, macrophages)
o adaptive immune system
▪ IL-2, IL-4, IL-17
▪ secreted by T- and B-lymphocytes
• can mediate activation, proliferation and differentiation of target cells
o pleiotropy
▪ 1 cytokine produces multiple effects
o redundancy
▪ > 1 cytokine induces the same effect
o synergy
▪ 2 / more cytokines wok together to induce an effect
o antagonism
▪ 1 cytokine can inactivate the effect of another
2
,1.3 SPECIFICITY IN THE CYTOKINE SYSTEM
specificity in the cytokine system:
• Ag-activation of a T cell changes expression pattern of
o chemokine receptors
o and the receptors for proliferation or differentiation inducing cytokines
⇒ only Ag-activated T cells are responsive
• cytokines are concentrated between the secreting and the target cell (= polarized secretion)
• half life of cytokines in extracellular milieu = very short
o cytokines act in a limited time frame
o and often only over a short distance
1.4 6 FAMILIES OF CYTOKINES
6 families of cytokines (+ associated receptor molecules):
• each family is distinguished by
o structure of ligand and receptor
o nature of signaling pathways induced
• 6 families
1. interleukine 1 family (+ immunoglobulin family receptors)
2. hematopoietin family cytokines (+ hematopoietin-type receptors)
3. interferon cytokine family (+ interferon-type receptors)
4. TNF familiy (+ TNF receptors)
5. IL-17 cytokine family (+ IL-17 receptors)
6. chemokines (+ chemokine receptors)
3
, 1.4.1 INTERLEUKINE 1 FAMILY
IL-1 receptor signaling:
• bind to immunoglobulin superfamily receptors
• signaling
1) IL-1 R is active when IL-1 binds
2) TIR domains are active
3) recruit adaptor protein MyD88
4) recruits IL-1 receptor activated kinases (IRAKs) and TGF-β-activated kinases 1 (TAK-1)
5) activation of AP-1, NF-κB transcription factors
6) cytokine expression
TIR = toll/IL-1 receptor domain
IRAK = IL-1Rc activated kinase
TRAF = TNFR-associated factor
TAK = TGFβ-activated kinase
TAB = TAK-1 binding protein
1.4.2 HEMATOPOIETIN (CLASS I) FAMILY CYTOKINES
hematopoietin (class I) family cytokines:
• originate from and affect many cells
o may signal: differentiation, activation, Ab-secretion, …
• share common structural motifs
o 4 helix bundle motif organized in 4 antiparallel helices
o classification based on helix length
▪ short helices: IL-2, IL-3, IL-4
▪ long helices: IL-6, IL-12
4
1.1 INTRODUCTION
regulators of the immune system:
• immune system is located at different sites in the body (primary and secondary lymphoid tissues)
• key to a successful immune system = rapid + effective communication between the cells
1.2 GENERAL PROPERTIES
general properties:
• messenger proteins of the immune system
• mediate the effector functions of the immune system
• provide protection against invading organisms
• regulate the intensity and duration of the response
• other names: monokines, lymphokines, interleukins
• chemokines are cytokines that induce chemotaxis (= directed migration)
• most are soluble proteins
1) released by one cell
2) bind to receptors on another cell
3) induce biological effects
• some are membrane-bound forms (TNF family)
• ligand-receptor interactions of very high affinity ⇒ very potent
• can act in several different ways
o endocrine action
▪ released into bloodstream to affect distant cells
▪ ex. IL-1 ⇒ fever
o paracrine action
▪ released to affect nearby cells
o autocrine action
▪ released
▪ but then bind to receptors on the cell that produced them
• can act in cascades
• the cells of the immune system are subject to control by a network of cytokine interactions
1
,1.2.1 BIOLOGICAL EFFECTS
biological effects:
• induction of proliferation or enhancing survival of target cells
• induction of migration
• changes in differentiation state
• functional classification
o innate immune system
▪ IL-1, TNF-α, CXCL8
▪ secreted by cells of innate immunity (ex. neutrophils, macrophages)
o adaptive immune system
▪ IL-2, IL-4, IL-17
▪ secreted by T- and B-lymphocytes
• can mediate activation, proliferation and differentiation of target cells
o pleiotropy
▪ 1 cytokine produces multiple effects
o redundancy
▪ > 1 cytokine induces the same effect
o synergy
▪ 2 / more cytokines wok together to induce an effect
o antagonism
▪ 1 cytokine can inactivate the effect of another
2
,1.3 SPECIFICITY IN THE CYTOKINE SYSTEM
specificity in the cytokine system:
• Ag-activation of a T cell changes expression pattern of
o chemokine receptors
o and the receptors for proliferation or differentiation inducing cytokines
⇒ only Ag-activated T cells are responsive
• cytokines are concentrated between the secreting and the target cell (= polarized secretion)
• half life of cytokines in extracellular milieu = very short
o cytokines act in a limited time frame
o and often only over a short distance
1.4 6 FAMILIES OF CYTOKINES
6 families of cytokines (+ associated receptor molecules):
• each family is distinguished by
o structure of ligand and receptor
o nature of signaling pathways induced
• 6 families
1. interleukine 1 family (+ immunoglobulin family receptors)
2. hematopoietin family cytokines (+ hematopoietin-type receptors)
3. interferon cytokine family (+ interferon-type receptors)
4. TNF familiy (+ TNF receptors)
5. IL-17 cytokine family (+ IL-17 receptors)
6. chemokines (+ chemokine receptors)
3
, 1.4.1 INTERLEUKINE 1 FAMILY
IL-1 receptor signaling:
• bind to immunoglobulin superfamily receptors
• signaling
1) IL-1 R is active when IL-1 binds
2) TIR domains are active
3) recruit adaptor protein MyD88
4) recruits IL-1 receptor activated kinases (IRAKs) and TGF-β-activated kinases 1 (TAK-1)
5) activation of AP-1, NF-κB transcription factors
6) cytokine expression
TIR = toll/IL-1 receptor domain
IRAK = IL-1Rc activated kinase
TRAF = TNFR-associated factor
TAK = TGFβ-activated kinase
TAB = TAK-1 binding protein
1.4.2 HEMATOPOIETIN (CLASS I) FAMILY CYTOKINES
hematopoietin (class I) family cytokines:
• originate from and affect many cells
o may signal: differentiation, activation, Ab-secretion, …
• share common structural motifs
o 4 helix bundle motif organized in 4 antiparallel helices
o classification based on helix length
▪ short helices: IL-2, IL-3, IL-4
▪ long helices: IL-6, IL-12
4
