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 auto-immune 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 that is absolutely required for signaling by IL-17 family cytokines. In FY 2010 we have generated mutant versions of this adaptor gene and packaged them into several different vector delivery systems. These mutant adaptors will be tested for their functions with several different assays we have established in FY 2010;the goal is to identify critical amino acid determinants on CIKS that can potentially be targeted for therapeutic intervention. To date relatively little is known about the receptors that mediate signaling by the various IL-17 cytokine family members. In FY2010 we have generated tagged versions of the receptor genes and packaged them into various vector delivery systems in order to probe interactions between various receptor chains and interaction with downstream signaling proteins, including CIKS. IL-25 is the most divergent member of the IL-17 cytokine family. It is associated with Th2-type innate and adaptive immune responses, but little is known about its regulation. In FY 2010 we have generated reporter mouse to help identify biologic contexts in which this cytokine is expressed and the cell types that are responsible.
