The role of Interleukin-1 associated kinase 1 in intestinal inflammation

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In inflammatory bowel diseases (IBD) intestinal inflammation is thought to be due to a dysregulated immune response to commensal bacteria due to a defective epithelial barrier function, which leads to overstimulation of epithelial cells, dendritic cells (DCs) and macrophages in the underlying lamina propria. Activated DCs present luminal antigens and promote the expansion and differentiation of proinflammatory effector T helper (Th)1 and Th17 cells while inhibiting regulatory T cell (Treg) generation. The resulting shift in the balance of regulatory to effector Th cells sustains the chronic inflammatory response. Interleukin-1 receptor associated kinases (IRAKs) are critically involved in signal transduction downstream of Toll-like receptors (TLRs) and the IL-1 receptor. Interaction of phosphorylated IRAK1 with tumor necrosis factor receptor associated factor 6 leads to the activation of nuclear factor k B (NFkB) and mitogen activated protein kinases. IRAK1 deficiency leads to a reduced but not abrogated inflammatory cytokine response to TLR and IL-1R triggering, but IRAK1 is not essential for antimicrobial defense making it a safe target for inhibition. Recent evidence support an important role of IRAK1 for autoimmune and inflammatory diseases.Our hypothesis is that IRAK1 is critically involved in the pathogenesis of intestinal inflammation in IBD and may be an attractive novel target for therapy. This hypothesis is supported by our preliminary results obtained with IRAK1-deficient mice in two inducible colitis models which demonstrate a non-redundant role of IRAK1 in the development of intestinal inflammation. It is not well understood how IRAK1 signaling in the different immune and non-immune cell types in the intestinal mucosa contributes to inflammation. Our results so far suggest that IRAK1 signaling in T cells plays a dominant role in colitis development, but also show a significant contribution of IRAK1 signaling in non-T cells, including innate immune cells and epithelial cells. In the proposed project we will therefore investigate: 1) the specific function of IRAK1 signaling in T cells and non-T cells for effector Th cell and Treg generation and intestinal accumulation during colitis, 2) the contribution of IRAK1 signaling in intestinal epithelial cells to colitis development, 3) the efficacy of an IRAK1/4 inhibitor in murine experimental colitis and 4) the expression of IRAK1 in intestinal mucosa of IBD patients as well as the role of IRAK1 for human Th cell differentiation.