Sandbox Reserved 777: Difference between revisions
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== Introduction == | == Introduction == | ||
Interleukin 10 (IL-10) belongs to a class of proteins called cytokines. Cytokines are chemical messengers that are produced by and act on cells of the immune system.'''(1)''' It is also part of the IL-10 family of cytokines, which also includes IL-19, IL-20, IL-22, IL-24 and IL-26. This grouping was made based on similarities in structure, function, and location of the encoding genes.'''(2)''' IL-10 has also previously been called cytokine synthesis inhibitory factor (CSIF) because of its anti-inflammatory properties and ability to inhibit the production of other cytokines.'''(3)''' The ability to limit the immune response to pathogens is crucial to preventing self-inflicted damage to the host. This cytokine is expressed in many eukaryotic hosts, as well as some viruses. A quick protein BLAST of the human IL-10 sequence reveals homology with IL-10 of many other primate species, as well as that found in bats, horses, elephants, rodents, sheep, cats and birds. The remainder of this page will focus on human IL-10. | Interleukin 10 (IL-10) belongs to a class of proteins called cytokines. Cytokines are chemical messengers that are produced by and act on cells of the immune system.'''(1)''' It is also part of the IL-10 family of cytokines, which also includes IL-19, IL-20, IL-22, IL-24 and IL-26. This grouping was made based on similarities in structure, function, and location of the encoding genes.'''(2)''' IL-10 has also previously been called cytokine synthesis inhibitory factor (CSIF) because of its anti-inflammatory properties and ability to inhibit the production of other cytokines.'''(3)''' The ability to limit the immune response to pathogens is crucial to preventing self-inflicted damage to the host. This cytokine is expressed in many eukaryotic hosts, as well as some viruses. A quick protein BLAST of the human IL-10 sequence reveals homology with IL-10 of many other primate species, as well as that found in bats, horses, elephants, rodents, sheep, cats and birds. The remainder of this page will focus on human IL-10. | ||
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== Structure == | == Structure == | ||
The cytokine structure is an intercalated dimer | The cytokine structure is an intercalated dimer of two identical polypeptide chains, each 178 amino acids in length.'''(4)''' The monomers are made up of six amphipathic helices, with two helices of one monomer interacting with four of the other monomer, creating two distinct domains.A four-helix bundle is made up of helices A, C, D and F’ (and A’, C’ D’ and F). This feature is a signature element of all helical cytokines.'''(5)''' The structure is stabilized by two disulfide bridges formed between the first and third cysteine residues and the second and fourth cysteine residues (Cys12 with Cys108, and Cys62 with Cys114). Reduction of the disulfide bonds in recombinant IL-10 has been shown to reduce helical content measured by circular dichroism and results in a lack of in vitro biological activity.'''(6)''' | ||
== Protein Expression == | == Protein Expression == | ||
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== Mechanism of Action == | == Mechanism of Action == | ||
Most hematopoietic cells express the IL-10 transmembrane receptors, IL-10R1 and IL-10R2. While IL-10R1 is specific only for IL-10 cytokine, IL-10R2 is also part of the receptor complexes for other ligands in the IL-10 family of cytokines. The affinity for IL-10 is higher for the IL-10R complex than for IL-10R1 alone.'''(2)''' IL-10 is a pleiotropic cytokine in that it has an effect on many different immune cells, including T-cells, B-cells, macrophages and mast cells.'''(3)''' When IL-10 binds the extracellular domain of the IL-10R1 receptor, two tyrosine-kinases, JAK1 and Tyk2 become phosphorylated, which in turn phosphorylate the internal domain of IL-10R1. This then binds the transcription factor STAT3, which becomes phosphorylated, dimerizes, and moves into the nucleus. In the nucleus, STAT3 binds to the promoters of various genes, resulting in decreased expression of inflammatory cytokines such as IFNγ, TNFα, and GM-CSF. IL-10R2 acts as an accessory subunit for signaling, rather than for ligand binding. It recruits the Tyk2 tyrosine kinase into the signaling complex described above.'''(4)''' | Most hematopoietic cells express the IL-10 transmembrane receptors, IL-10R1 and IL-10R2. While IL-10R1 is specific only for IL-10 cytokine, IL-10R2 is also part of the receptor complexes for other ligands in the IL-10 family of cytokines. The affinity for IL-10 is higher for the IL-10R complex than for IL-10R1 alone.'''(2)''' IL-10 is a pleiotropic cytokine in that it has an effect on many different immune cells, including T-cells, B-cells, macrophages and mast cells.'''(3)''' When IL-10 binds the extracellular domain of the IL-10R1 receptor, two tyrosine-kinases, JAK1 and Tyk2 become phosphorylated, which in turn phosphorylate the internal domain of IL-10R1. This then binds the transcription factor STAT3, which becomes phosphorylated, dimerizes, and moves into the nucleus. In the nucleus, STAT3 binds to the promoters of various genes, resulting in decreased expression of inflammatory cytokines such as IFNγ, TNFα, and GM-CSF. IL-10R2 acts as an accessory subunit for signaling, rather than for ligand binding. It recruits the Tyk2 tyrosine kinase into the signaling complex described above.'''(4)''' | ||
IL-10 bound to IL-10R1 forms a tetramer, made up of the dimeric two-domain IL-10 molecule and two IL-10R1 receptors.'''(4)''' | |||
== Implications or Possible Application == | == Implications or Possible Application == | ||
