IL-17 family cytokines such as IL-17 and IL-25 have been implicated in the pathogenesis of inflammatory and auto-immune diseases. In order to devise strategies to disable signaling by these cytokines in disease, it is imperative to understand the pathways and molecular mechanisms by which these cytokines transmit signals in target cells to effect gene expression. In FY 2009 we have been able to directly demonstrate that IL-17 signaling requires the CIKS adaptor protein to activate NF-kappaB and other specific downstream targets;some of these findings have also been reported by others. In FY 2009 we have also been able to show that IL-25 signals via the CIKS adaptor as well, even though IL-25 and IL-17 are part very different adaptive immune responses. IL-25 contributes to T helper 2 cell (Th2) directed responses, while IL-17 is central to Th17 responses;these two responses may even oppose each other. Specifically we have been able to demonstrate that the CIKS adaptor is transiently recruited to the IL-17RB chain upon stimulation of cells with IL-25;these experiments were carried out with cells transfected with expression constructs encoding molecularly tagged IL-17RB and CIKS. Finally we have been able to demonstrate that IL-25 can directly induce Th2-type cytokines in populations of bone marrow derived dendritic cells and macrophages and that it does so in a CIKS-dependent manner;identification of IL-25 responsive cells is critical as the direct targets of IL-25 have not been clearly defined in the past.
