NLRP12 Regulation of COX-2 in Colitis and Colon Cancer Development

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DESCRIPTION (provided by applicant): Colorectal cancer (CC) is a leading contributor to cancer-related deaths in the United States and is a major complication of inflammatory bowel diseases (IBD), such as ulcerative colitis (UC). IBD are commonly associated with the exaggerated production of inflammatory cytokines, which are regulated by the activation of various cell signaling pathways and the NF-(B family of transcription factors. The NLR (nucleotide binding domain and leucine-rich-repeat-containing or NOD-like receptor) family of proteins has received much attention in IBD research due to the genetic association of NOD2 with Crohns' disease. We found that NLRP12, a new NLR family member, is expressed in monocytes, granulocytes, and dendritic cells and acts as a negative regulator of inflammation by suppressing NF-(B activation via multiple mechanisms, including the induction of proteasome mediated degradation of NIK (NF-(B inducing kinase). Moreover, the loss of NLRP12 results in elevated NIK, leading to the constitutive expression of COX-2 which is the inducible form of the rate-limiting enzyme responsible for prostaglandin (PG) synthesis. COX-2 expression and PGE2 production are elevated in IBD and CC, yet their precise role in the development of these diseases is somewhat controversial. The absence of COX-2 leads to increased susceptibility of colitis in murine models of UC. However, COX-2-derived PGE2 promotes growth and invasion of colorectal carcinoma and several COX-2 inhibitors have been shown to suppress the development of colorectal tumors. Preliminary data from our lab indicates that mice lacking NLRP12 are significantly more susceptible to the development of colitis and display greater colon tumorigenesis than their wildtype counterparts. It is unclear if this is due to elevated COX-2-derived PG levels, enhanced inflammatory cytokine production (e.g. IL-1( and IL-6), or a combination of these two elements. The goal of this proposal is to explore the contribution of COX-2 metabolites and other inflammatory factors negatively regulated by NLRP12 in the development of UC and CC and to identify the mechanism behind NLRP12 regulation of NIK. Aim 1 will examine if NLRP12 regulates COX-2 metabolites in UC and CC models. Aim 2 will examine if the regulation of NIK and/or IRAK by NLRP12 plays a role in the development of UC and/or CC. Aim 3 will explore the mechanism by which NLRP12 regulates the NIK pathway.