IL-17 family cytokines such as IL-17 (aka IL-17A), the closely related IL-17F, and IL-25 have been implicated in the pathogenesis of various inflammatory and autoimmune diseases. In order to devise strategies to disable signaling by these cytokines in diseases, it is imperative to understand the pathways and molecular mechanisms by which these cytokines transmit signals in target cells to effect gene expression. In the past we have cloned an adaptor protein (CIKS) and demonstrated that this protein is absolutely required for signaling by IL-17 family cytokines and their pathogenic effects in disease contexts. We previously identified a critical N-terminal domain within the CIKS adaptor protein that mediates a functionally relevant interaction with Traf6, another adaptor protein. Traf6 in turn is required for activation of the NF-kappaB transcription factor, an important downstream effector of IL-17-induced expression of numerous target genes. IL-17 cytokines have also recently been shown to have a critical role in the development of psoriasis. It was therefore unexpected when a recent GWAS study for psoriasis identified an SNP in CIKS as a risk factor for psoriasis, even though that particular SNP predicted a mutation that impaired the ability of CIKS to interact with Traf6 and to activate NF-kappaB. However in FY 2012 we were able to show that although signaling by IL-17 was impaired by this mutant CIKS, it did not impair the genetic response to the combined action of IL-17 plus TNFa. Since psoriatic inflammation also critically involves TNFa, this particular CIKS mutant would thus not be expected impair the inflammatory signals transmitted by IL-17 cytokines in this inflammatory context. It is possible however that this mutant raises the risk of psoriasis because it is likely to impair the ability of low levels of IL-17 cytokines, in the absence of TNFa, to maintain basal homeostatic barrier functions. In turn this raises the specter of environmental insults more readily leading to inflammation and high expression of both IL-17 and TNFa. This model would explain the heightened risk for psoriasis associated with this particular CIKS mutant.
