Cytokines are key messenger molecules in cell-to-cell communication and are involved in various aspects of the immune system such as maintaining homeostasis and mediating and resolving pathologic conditions. IL-17 (Interleukin-17) family is a group of cytokines sharing homology in amino acid sequences with highly conserved cysteine residues critical to their 3-dimensional shape. IL-17, the signature cytokine secreted by Th17 cells, is required for host defence against extracellular bacterial and fungal infections, and contributes to the pathogenesis of various autoimmune inflammatory diseases. IL-17 has become an important target for treating different forms of inflammatory disorders. Recent clinical trials with agents that target IL-17/IL-17R, the upstream regulation pathways of IL-17 expression and the downstream signaling pathways of IL-17 hold promise for treating autoimmune diseases. So far, six members, IL-17A (commonly refer to IL-17), IL-17B, IL-17C, IL-17D, IL-17E (also called IL-25) and IL-17F, have been identified. The IL-17R family contains five receptor subunits, IL-17RA–IL-17RE. Both IL-17 members and IL-17Rs have little homology to other known cytokines or cytokine receptors, and are classified as new cytokine and cytokine receptor families.IL-17 signals through a heteromeric receptor complex formed by IL-17R (IL-17RA) and IL-17RC, which are single-pass transmembrane proteins expressed by a variety of cells including astrocytes and microglia. IL-17RA can be bound by both IL-17A and IL-17F, but with 10-fold more affinity for IL-17A than for IL-17F. While both IL-17E and IL-17B bind IL-17RB, to induce Th2 cytokines, the ligand for IL-17RD is still unknown. IL-17C may be the ligand for IL-17RE, but the functional link needs to be identified. Binding of the first IL-17 receptor subunit to the ligand modulates the affinity and specificity of the second-binding event, thereby promoting heterodimeric versus homodimeric complex formation. Three remaining cytokines in the IL-17 family, IL-17B, IL-17C and IL-17D, currently are poorly studied with regards to their biological function and receptors.IL-17C which binds to the IL-17RE–IL-17RA heterodimeric complex is also important for host defence and autoimmunity (Ref.1, 2, 3&4).
References:
1.Signaling of interleukin-17 family cytokines in immunity and inflammation.
Chang SH, Dong C. Cell Signal. 2011 Jul;23(7):1069-75. 2.IL-17/IL-17 receptor system in autoimmune disease: mechanisms and therapeutic potential. Zhu S, Qian Y. Clin Sci (Lond). 2012 Jun;122(11):487-511. 3.IL-17 receptor signaling and T helper 17-mediated autoimmune demyelinating disease. Zepp J, Wu L, Li X. Trends Immunol. 2011 May; 32(5):232-9. 4.Structure and signalling in the IL-17 receptor family. Gaffen SL. Nat Rev Immunol. 2009 Aug; 9(8):556-67. 5.IL-17 and IL-22: siblings, not twins. Eyerich S, Eyerich K, Cavani A, Schmidt-Weber C. Trends Immunol. 2010 Sep;31(9):354-61. 6.IL-17RC: a partner in IL-17 signaling and beyond. Ho AW, Gaffen SL. Semin Immunopathol. 2010 Mar; 32(1):33-42. 7.IL-17F: regulation, signaling and function in inflammation. Chang SH, Dong C. Cytokine. 2009 Apr;46(1):7-11. 8.IL-17 activates the canonical NF-kappaB signaling pathway in autoimmune B cells of BXD2 mice to upregulate the expression of regulators of G-protein signaling 16. Xie S, Li J, Wang JH, Wu Q, Yang P, Hsu HC, Smythies LE, Mountz JD. J Immunol. 2010 Mar 1; 184(5):2289-96. 9.Differential regulation of the IL-17 receptor by gammac cytokines: inhibitory signaling by the phosphatidylinositol 3-kinase pathway. Lindemann MJ, Hu Z, Benczik M, Liu KD, Gaffen SL. J Biol Chem. 2008 May 16;283(20):14100-8. doi: 10.1074/jbc.M801357200. 10.IL-17 receptor signaling inhibits C/EBPbeta by sequential phosphorylation of the regulatory 2 domain. Shen F, Li N, Gade P, Kalvakolanu DV, Weibley T, Doble B, Woodgett JR, Wood TD, Gaffen SL. Sci Signal. 2009 Feb 24;2(59):ra8. doi: 10.1126/scisignal.2000066. 11.Structure-function relationships in the IL-17 receptor: implications for signal transduction and therapy. Shen F, Gaffen SL. Cytokine. 2008 Feb;41(2):92-104. Epub 2008 Jan 4. 12.TRAF6 dependent Act1 phosphorylation by the IKK-related kinases suppresses IL-17-induced NF-κB activation. Qu F, Gao H, Zhu S, Shi P, Zhang Y, Liu Y, Jallal B, Yao Y, Shi Y, Qian Y. Mol Cell Biol. 2012 Jul 30. 13.IL-17R signaling: new players get in on the Act1. May MJ. Nat Immunol. 2011 Aug 18; 12(9):813-5. doi: 10.1038/ni.2093. 14.A comparative study of ofloxacin and pivmecillinam in acute exacerbations of chronic bronchitis. Egede F, Kristensen I. Scand J Infect Dis Suppl. 1990; 68:46-9.
|