immune cytokines
Cytokines are small proteins that regulate and mediate immunity, inflammation, and hematopoiesis. They are secreted de novo in response to immune stimuli, and usually act briefly, locally, at very low concentrations (the exception being endocrine action at distant cells). All cytokines possess four conserved cysteine residues, and are divided into two families based upon the contiguity (CC) or separation of cysteine residues (CXC).
The orchestration and regulation of cytokine production during inflammatory responses constitutes a key determinant of both the resolution of challenge and the limitation of host tissue damage. Cytokines bind to specific membrane receptors, which then signal the cell via second messengers, often tyrosine kinases, to alter cellular activity (gene expression). Cytokines are often produced in cascades.
Tables Immune Cytokines Fc receptors Immunoglobulins Interferons
▼ actions : chemokine : chemokine family receptors : classification of cytokines : colony-stimulating factors (CSF) : cytokine cascade : cytokine effects : cytokine receptors : cytokine secreting cells : distance of cytokine action : granulocyte colony-stimulating factor (G-CSF) : granulocyte-macrophage colony-stimulating factor (GM-CSF) : hematopoietin family receptors : interleukins, interleukins as largest group : interferon family receptors (IFNR) : largest group of cytokines : lymphokine : lymphotoxins : macrophage colony-stimulating factor (M-CSF) : mechanism of cytokine action : monokine : receptors : search for novel cytokines : target cells : tumor necrosis family receptors
(TNFR) ▼
Actions of cytokines include:
a) up- or down-regulation of the expression of membrane proteins (including cytokine receptors),
b) secretion of effector molecules: histamine release; antibody secretion - IgA, IgG1, and IgE synthesis; IL-1 synthesis; cytokine production; MHC Class II; and CAM expression
c) cellular proliferation
d) chemotaxis of neutrophils, monocytes, and T cells
e) cellular differentiation
f) inflammation
g) phagocytosis
h) death of tumor cells
i) elimination of pathogens
Cytokines are classified according to the cells that produce them:
a) Lymphokines - produced by lymphocytes
b) Monokines - produced by monocytes,
c) Chemokines - chemotactic activities
d) Interleukins - manufactured by one leukocyte to act on other leukocytes.
The cells that produce cytokines include B cells, T cells, dendritic cells, NK, Tc, Th, Th1, Th2, endothelial cells, mast cells, plasma cells, progenitor, marrow stroma, thymus stroma, and tumor cells, along with fibroblasts, leukocytes, monocytes, and macrophages.
Cytokine function may be targetted at:
a) The cells that secrete them (autocrine action),
b) Local cells (paracrine action),
c) Distant cells (endocrine action).
Target cells include: B cells, T cells, NK, Tc, Th, Th2, stem, mast cells, plasma cells, progenitor, tumor cells, phagocytes, neutrophils, monocytes, and macrophages.
Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine secreted by several cell types, including mononuclear cells of the immune system and pituitary cells in the brain. Functional promoter polymorphisms in the MIF gene affect the clinical presentation of systemic sclerosis (SSc, scleroderma) and confer susceptibility to systemic lupus erythematosis (SLE). MIF counteracts cortisol-induced inhibition of inflammatory cytokine secretion, and employs the CD74 receptor.
Cytokines bind to specific membrane receptors:
a) Hematopoietin family receptors - dimers or trimers with conserved cysteines in their extracellular domains and a conserved Trp-Ser-X-Trp-Ser sequence.
The two subunits are i) cytokine-specific, and ii) signal transducing.
Cytokine binding promotes dimerization of the alpha and beta subunits, which then associate with cytoplasmic tyrosine kinases to phosphorylate proteins and activate mRNA transcription. Examples - receptors for IL-2 through IL-7 and GM-CSF.
Colony-stimulating factors (CSFs) are glycoprotein molecules that support growth of hematopoietic colonies. Interleukin 3 (IL-3) exhibits broad activity in the proliferation and differentiation of erythroid, megakaryocytic, and myeloid lineage progenitor cells.
Macrophage colony-stimulating factor (M-CSF, CSF1) acts selectively on the macrophage lineage, while granulocyte colony-stimulating factor (G-CSF) acts selectively on cells of the granulocyte lineage.
Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have pleiotropic activating effects on mature leukocytes, which can improve leukocyte function, facilitating eradication of microbial infections. G-CSF activates neutrophils, while GM-CSF activates neutrophils, eosinophils, and monocyte/macrophages.
G-CSF is a 19.6 kDA glycoprotein that exists in two forms, comprising either 174 or 180 amino-acids. It is produced in a number of different tissues and stimulates granulopoietic proliferation and differentiation in the bone marrow. GM-CSF is a 14.6 kDa globular protein of 128 amino acids that contains two intramolecular disulfide bonds and two potential N-linked glycosylation sites. It is produced by endothelial cells, monocytes, fibroblasts and T-lymphocytes. GM-CSF is a hematopoietic growth factor that stimulates the development of macrophages and neutrophils, and inhibits neutrophil migration while enhancing the functional activity of the mature end-cells. It also promotes the proliferation and development of early erythroid megakaryocytic and eosinophilic progenitor cells.
b) Interferon (IFN) family receptors have the conserved cysteine residues but not the Trp-Ser-X-Trp-Ser sequence, and include the receptors for IFNα, IFNb, and IFNγ.
c) Tumor Necrosis Factor family receptors possess four extracellular domains, and include receptors for soluble TNFα and TNFβ as well as membrane-bound CD40 (important for B cell activation and macrophage activation) and Fas (which signals the cell to undergo apoptosis). TNFα is lymphotoxin β (LT), where the lymphotoxins occur either as homotrimers of LT-α (LT-α3) or as heterotrimers of one LT-α subunit plus two LT-β subunits (LT-α,β2).[s]
d) Chemokine family receptors have seven transmembrane helices and interact with G protein. This family includes receptors for IL-8, MIP-1 and RANTES. Chemokine receptors CCR5 and CXCR4 are used by HIV to preferentially enter either macrophages or T cells.
Cytokines are often produced in cascades, as one cytokine stimulates its target cells to produce additional cytokines. Cytokines are redundant in their activity, in that different cytokines can stimulated similar functions. Different cell types may secrete the same cytokine, or for a single cytokine may act on several different cell types (pleiotropy). Cytokines can also act synergistically with two or more cytokines acting together, or antagonistically with cytokines causing opposing activities.
Interleukins comprise the largest group of cytokines, stimulating proliferation and differentiation of immune cells. The group includes Interleukin 1 (IL-1), which activates T cells; IL-2, which stimulates proliferation of antigen-activated T and B cells; IL-4, IL-5, and IL-6, which stimulate proliferation and differentiation of B cells; Interferon gamma (IFNγ), which activates macrophages; and IL-3, IL-7 and Granulocyte Monocyte Colony-Stimulating Factor (GM-CSF), which stimulate hematopoiesis.
Short half lives, low plasma concentrations, pleiotropy, and redundancy combine to make the isolation and characterization of cytokines difficult. Search for novel cytokines is often conducted at the DNA level, identifying genes that are similar to known cytokine genes.
▲ actions : chemokine : chemokine family receptors : classification of cytokines : colony-stimulating factors (CSF) : cytokine cascade : cytokine effects : cytokine receptors : cytokine secreting cells : distance of cytokine action : granulocyte colony-stimulating factor (G-CSF) : granulocyte-macrophage colony-stimulating factor (GM-CSF) : hematopoietin family receptors : interleukins, interleukins as largest group : interferon family receptors (IFNR) : largest group of cytokines : lymphokine : lymphotoxins : macrophage colony-stimulating factor (M-CSF) : mechanism of cytokine action : monokine : receptors : search for novel cytokines : target cells : tumor necrosis family receptors (TNFR) ▲
Tables Immune Cytokines Cell signaling Receptor Tyrosine Kinases(RTK) Second Messengers Phosphate-handling Enzymes Cell Adhesion Molecules (CAM) .
· adenylyl (adenylate) cyclase ф antibodies ф antigen ф B cells · cadherins · calcium ions · cAMP-dependent protein kinase · CDKs ф cellular response · chemotaxis ф class-switch recombination ф clonal selection ф complement system ф costimulation · cyclin-dependent kinases · cytokine receptors · DAG ф dendritic cells · diacylglycerol · DNA ligases · ERKs · GPCRs · GPCR families ф granulocytes · guanylate cyclases · guanyl cyclase ф helper T cell ф hematopoiesis ф humoral immunity · Ig superfamily ф immune response ф inflammatory response · inositol triphosphate · integrins · IP3 ф leukocytes ф leukocyte adhesion cascade ф lymphokines ф macrophages · MAP kinases ф macrophages ф MHC ф migration · mitogen activated protein kinases ф monocytes ф neutrophils ф pathogens ф pattern-recognition receptors ф phagocyte · phosphatases · phosphodiesterases ф plasma cells · phospolipases · phosphorylation · PKA · PKC · phospholipase C-gamma · protein kinase A · protein kinase C · protein tyrosine kinases (PTKs) ф receptors · receptor tyrosine kinases · second messengers · second messenger cAMP · second messenger cGMP · selectins ф signaling · signal transduction ф surface receptors ф T cells · TNFs · two-component systems ·
Tables Fc receptors Immune Cytokines Immunoglobulins Interferons Cell Adhesion Molecules Cell signaling Receptor Tyrosine Kinases (RTKs) Receptor Signal Transduction Second Messengers 
The orchestration and regulation of cytokine production during inflammatory responses constitutes a key determinant of both the resolution of challenge and the limitation of host tissue damage. Cytokines bind to specific membrane receptors, which then signal the cell via second messengers, often tyrosine kinases, to alter cellular activity (gene expression). Cytokines are often produced in cascades.
Tables Immune Cytokines Fc receptors Immunoglobulins Interferons
▼ actions : chemokine : chemokine family receptors : classification of cytokines : colony-stimulating factors (CSF) : cytokine cascade : cytokine effects : cytokine receptors : cytokine secreting cells : distance of cytokine action : granulocyte colony-stimulating factor (G-CSF) : granulocyte-macrophage colony-stimulating factor (GM-CSF) : hematopoietin family receptors : interleukins, interleukins as largest group : interferon family receptors (IFNR) : largest group of cytokines : lymphokine : lymphotoxins : macrophage colony-stimulating factor (M-CSF) : mechanism of cytokine action : monokine : receptors : search for novel cytokines : target cells : tumor necrosis family receptors
(TNFR) ▼
Actions of cytokines include:
a) up- or down-regulation of the expression of membrane proteins (including cytokine receptors),
b) secretion of effector molecules: histamine release; antibody secretion - IgA, IgG1, and IgE synthesis; IL-1 synthesis; cytokine production; MHC Class II; and CAM expression
c) cellular proliferation
d) chemotaxis of neutrophils, monocytes, and T cells
e) cellular differentiation
f) inflammation
g) phagocytosis
h) death of tumor cells
i) elimination of pathogens
Cytokines are classified according to the cells that produce them:
a) Lymphokines - produced by lymphocytes
b) Monokines - produced by monocytes,
c) Chemokines - chemotactic activities
d) Interleukins - manufactured by one leukocyte to act on other leukocytes.
The cells that produce cytokines include B cells, T cells, dendritic cells, NK, Tc, Th, Th1, Th2, endothelial cells, mast cells, plasma cells, progenitor, marrow stroma, thymus stroma, and tumor cells, along with fibroblasts, leukocytes, monocytes, and macrophages.
Cytokine function may be targetted at:
a) The cells that secrete them (autocrine action),
b) Local cells (paracrine action),
c) Distant cells (endocrine action).
Target cells include: B cells, T cells, NK, Tc, Th, Th2, stem, mast cells, plasma cells, progenitor, tumor cells, phagocytes, neutrophils, monocytes, and macrophages.
Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine secreted by several cell types, including mononuclear cells of the immune system and pituitary cells in the brain. Functional promoter polymorphisms in the MIF gene affect the clinical presentation of systemic sclerosis (SSc, scleroderma) and confer susceptibility to systemic lupus erythematosis (SLE). MIF counteracts cortisol-induced inhibition of inflammatory cytokine secretion, and employs the CD74 receptor.
Cytokines bind to specific membrane receptors:
a) Hematopoietin family receptors - dimers or trimers with conserved cysteines in their extracellular domains and a conserved Trp-Ser-X-Trp-Ser sequence.
The two subunits are i) cytokine-specific, and ii) signal transducing.
Cytokine binding promotes dimerization of the alpha and beta subunits, which then associate with cytoplasmic tyrosine kinases to phosphorylate proteins and activate mRNA transcription. Examples - receptors for IL-2 through IL-7 and GM-CSF.
Colony-stimulating factors (CSFs) are glycoprotein molecules that support growth of hematopoietic colonies. Interleukin 3 (IL-3) exhibits broad activity in the proliferation and differentiation of erythroid, megakaryocytic, and myeloid lineage progenitor cells.
Macrophage colony-stimulating factor (M-CSF, CSF1) acts selectively on the macrophage lineage, while granulocyte colony-stimulating factor (G-CSF) acts selectively on cells of the granulocyte lineage.
Granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have pleiotropic activating effects on mature leukocytes, which can improve leukocyte function, facilitating eradication of microbial infections. G-CSF activates neutrophils, while GM-CSF activates neutrophils, eosinophils, and monocyte/macrophages.
G-CSF is a 19.6 kDA glycoprotein that exists in two forms, comprising either 174 or 180 amino-acids. It is produced in a number of different tissues and stimulates granulopoietic proliferation and differentiation in the bone marrow. GM-CSF is a 14.6 kDa globular protein of 128 amino acids that contains two intramolecular disulfide bonds and two potential N-linked glycosylation sites. It is produced by endothelial cells, monocytes, fibroblasts and T-lymphocytes. GM-CSF is a hematopoietic growth factor that stimulates the development of macrophages and neutrophils, and inhibits neutrophil migration while enhancing the functional activity of the mature end-cells. It also promotes the proliferation and development of early erythroid megakaryocytic and eosinophilic progenitor cells.
b) Interferon (IFN) family receptors have the conserved cysteine residues but not the Trp-Ser-X-Trp-Ser sequence, and include the receptors for IFNα, IFNb, and IFNγ.
c) Tumor Necrosis Factor family receptors possess four extracellular domains, and include receptors for soluble TNFα and TNFβ as well as membrane-bound CD40 (important for B cell activation and macrophage activation) and Fas (which signals the cell to undergo apoptosis). TNFα is lymphotoxin β (LT), where the lymphotoxins occur either as homotrimers of LT-α (LT-α3) or as heterotrimers of one LT-α subunit plus two LT-β subunits (LT-α,β2).[s]
d) Chemokine family receptors have seven transmembrane helices and interact with G protein. This family includes receptors for IL-8, MIP-1 and RANTES. Chemokine receptors CCR5 and CXCR4 are used by HIV to preferentially enter either macrophages or T cells.
Cytokines are often produced in cascades, as one cytokine stimulates its target cells to produce additional cytokines. Cytokines are redundant in their activity, in that different cytokines can stimulated similar functions. Different cell types may secrete the same cytokine, or for a single cytokine may act on several different cell types (pleiotropy). Cytokines can also act synergistically with two or more cytokines acting together, or antagonistically with cytokines causing opposing activities.
Interleukins comprise the largest group of cytokines, stimulating proliferation and differentiation of immune cells. The group includes Interleukin 1 (IL-1), which activates T cells; IL-2, which stimulates proliferation of antigen-activated T and B cells; IL-4, IL-5, and IL-6, which stimulate proliferation and differentiation of B cells; Interferon gamma (IFNγ), which activates macrophages; and IL-3, IL-7 and Granulocyte Monocyte Colony-Stimulating Factor (GM-CSF), which stimulate hematopoiesis.
Short half lives, low plasma concentrations, pleiotropy, and redundancy combine to make the isolation and characterization of cytokines difficult. Search for novel cytokines is often conducted at the DNA level, identifying genes that are similar to known cytokine genes.
▲ actions : chemokine : chemokine family receptors : classification of cytokines : colony-stimulating factors (CSF) : cytokine cascade : cytokine effects : cytokine receptors : cytokine secreting cells : distance of cytokine action : granulocyte colony-stimulating factor (G-CSF) : granulocyte-macrophage colony-stimulating factor (GM-CSF) : hematopoietin family receptors : interleukins, interleukins as largest group : interferon family receptors (IFNR) : largest group of cytokines : lymphokine : lymphotoxins : macrophage colony-stimulating factor (M-CSF) : mechanism of cytokine action : monokine : receptors : search for novel cytokines : target cells : tumor necrosis family receptors (TNFR) ▲
Tables Immune Cytokines Cell signaling Receptor Tyrosine Kinases(RTK) Second Messengers Phosphate-handling Enzymes Cell Adhesion Molecules (CAM) .
· adenylyl (adenylate) cyclase ф antibodies ф antigen ф B cells · cadherins · calcium ions · cAMP-dependent protein kinase · CDKs ф cellular response · chemotaxis ф class-switch recombination ф clonal selection ф complement system ф costimulation · cyclin-dependent kinases · cytokine receptors · DAG ф dendritic cells · diacylglycerol · DNA ligases · ERKs · GPCRs · GPCR families ф granulocytes · guanylate cyclases · guanyl cyclase ф helper T cell ф hematopoiesis ф humoral immunity · Ig superfamily ф immune response ф inflammatory response · inositol triphosphate · integrins · IP3 ф leukocytes ф leukocyte adhesion cascade ф lymphokines ф macrophages · MAP kinases ф macrophages ф MHC ф migration · mitogen activated protein kinases ф monocytes ф neutrophils ф pathogens ф pattern-recognition receptors ф phagocyte · phosphatases · phosphodiesterases ф plasma cells · phospolipases · phosphorylation · PKA · PKC · phospholipase C-gamma · protein kinase A · protein kinase C · protein tyrosine kinases (PTKs) ф receptors · receptor tyrosine kinases · second messengers · second messenger cAMP · second messenger cGMP · selectins ф signaling · signal transduction ф surface receptors ф T cells · TNFs · two-component systems ·
Tables Fc receptors Immune Cytokines Immunoglobulins Interferons Cell Adhesion Molecules Cell signaling Receptor Tyrosine Kinases (RTKs) Receptor Signal Transduction Second Messengers
Labels: CC, CXC, cytokines, hematopoeisis, immune response, inflammation