Lay Summary
Proposal No. IBD-0210R2
Principal Investigator: Xiaojing Ma, Ph.D.
Applicant Organization: Weill Medical College of Cornell University (New York, New York, U.S.A.)
Project Title: The Crohn’s disease-associated NOD23020insC mutant has an acquired activity as an inhibitor of IL-10 production
Period of Award: October 1, 2007 - March 31, 2009
Nucleotide-binding oligomerization domain 2 (NOD2) is a monocyte-restricted member of a protein family that are critically involved in host sensing of bacterium-derived products such as peptidoglycan (PGN). Certain mutations in the NOD2 gene underline the occurrence of inflammatory bowel disease (IBD) in a substantial group of patients with Crohn’s disease (CD). One of the mutations, designated 3020insC, which results in a slightly smaller NOD2 protein, is strongly associated with susceptibility to CD. CD is characterized by an exaggerated T cell-driven immune response in the intestines resulting from an imbalance in the production of proinflammatory and antiinflammatory factors of the immune system. Two recent studies demonstrated that the mononuclear cells of CD patients carrying the 3020insC mutation are defective in the production of Interleukin-10 (IL-10), a major immune regulator that controls inflammation. The chronically impaired IL-10 production may lead to persistent inflammation that causes damage to the intestines characteristic of CD. Our group has recently obtained novel data suggesting that, contrary to the common belief, 3020insC is not simply a mutation that results in “loss-of-function”. Instead, it can act as an inhibitor of IL-10 production, which could lead to excessive inflammation in the intestines. We propose to investigate how 3020insC alters the regulation of IL-10 production in mononuclear cells in CD patients. It is a very important question to address because understanding how the mutant 3020insC alters IL-10 synthesis could help us identify specific and sensitive points of the regulatory pathway(s) as potential therapeutic targets in the treatment of CD by lessening the exacerbated inflammation driven by deficiency in IL-10.