Sandbox Reserved 777: Difference between revisions

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.<ref>Sabat, Robert. IL-10 family of cytokines.  Cytokine Growth Factor Rev. 2010; 21:315–324</ref> 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.<ref>de Waal Malefyt R, Abrams J, Bennett B, Figdor CG, de Vries, JE.  Interleukin 10 (IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J. Exp. Med. 1991 Nov; 174(5):1209-1220</ref> 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.<scene name='56/564053/Il_10-il_10r1/3'>IL-10 bound to IL-10R1</scene> forms a tetramer, made up of the dimeric two-domain IL-10 molecule and two IL-10R1 receptors.<ref>Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A. Interleukin-10 and the Interleukin-10 receptor. Annu. Rev. Immunol. 2001.19:683-765</ref>The IL-10R1 receptor in this image is shown in dark blue.

Interleukin-10 plays a role in a number of diseases, particularly those with an autoimmune facet. One example of this is Crohn’s disease, a chronic inflammatory bowel condition in which the immune system attacks the gastrointestinal tract.  It has been shown that IL-10 production in patients with severe Crohn’s is down regulated.'''(9)'''  In a phase I clinical trial,'''(10)''' patients were treated with a Lactobacillus species that had been genetically modified to encode human IL-10. Patients reported a decrease in disease activity with no serious adverse events. On the other hand, patients with Systemic Lupus Erythematosus (SLE) have been found to have circulating IL-10 levels 9-fold higher than normal controls. It is believed that increased production of IL-10 stimulates production of hyperactive B-cells, which in turn leads to excessive autoantibody production. These autoantibodies trigger inflammatory responses that cause tissue damage.  In fact, mouse models of SLE have shown that administration of anti-IL-10 monoclonal antibodies  reduces morbidity due to disease, while giving additional IL-10 speeds the progression of disease.'''(11)'''  

9) Correa I, Veny M, Esteller M, Piqué JM, Yagüe J, Panés J, Salas A. Defective IL-10 production in severe phenotypes of Crohn’s disease. J Leukoc Biol. 2009 May; 85(5):896-903