The roles of MKP-1 in Gram-negative bacterial sepsis and colitis

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DESCRIPTION (provided by applicant): Dysregulation of the inflammatory response plays an important role in the pathogenesis of a plethora of human diseases, including septic shock and inflammatory bowel disease (IBD). Mitogen-activated protein kinase phosphatase (MKP)-1 is crucial for restraining the inflammatory response during bacterial infection. MKP-1 acts as an inducible negative regulator of p38 and JNK, and serves to restrict the production of pro-inflammatory cytokines. MKP-1-deficient (MKP-1-/-) mice exhibit a more robust inflammatory response than do wild-type mice when challenged with both toll-like receptor ligands and bacteria. Since inflammation facilitates the containment and clearance of microbial pathogens, we reasoned that MKP-1-/- mice should exhibit more efficient killing of invading pathogens. Surprisingly, when infected with Escherichia coli, MKP-1-/- mice exhibited substantially greater bacterial burdens than do wild-type mice in spite of a more robust inflammatory response. These data suggest that MKP-1 not only functions as a crucial anti-inflammatory regulator but also plays an important role in orchestrating the bactericidal activity of the innate immune mechanism. In addition to inflammatory cytokines, MKP-1-/- mice also produce substantially higher levels of the anti-inflammatory cytokine IL-10. This led us to hypothesize that excessive IL-10 production impairs the antimicrobial defense in MKP-1-/- mice. To understand the role of IL-10 in MKP-1-/- mice, we generated mice that lack both the IL-10 and MKP-1 genes. IL-10-/- mice housed in conventional but not pathogen-free conditions are known to develop colitis associated with rectal prolapse. Conversely, deletion of both MKP-1 and IL-10 caused severe rectal prolapse even in pathogen-free conditions. The MKP-1/IL-10 double knockout mice also developed ocular abnormalities, a novel phenotype resembling the ocular manifestation of IBD. Taken together, these data suggest that MKP-1 deficiency exacerbates the colitis phenotype of IL-10-/- mice. We propose to define the molecular mechanisms underlying the bactericidal defects of MKP-1-/- mice and to define the role of MKP-1 in the pathogenesis of colitis using the IL-10-/- mouse model of IBD. Our specific aims are to determine: 1). The defects in the innate immune system underlying the faulty bactericidal activity of MKP-1-/- mice; 2) Whether excessive IL-10 production contributes to the defects in the bactericidal activity of MKP-1-/- mice; and 3) Whether MKP-1 deficiency exacerbates the severity of colitis in IL-10-/- mice. The proposed studies will unravel critical regulatory mechanisms that govern the immune response to infection and prevent chronic enterocolitis and may lead to novel strategies for the treatment of sepsis and IBD. PUBLIC HEALTH RELEVANCE: Abnormal immune responses are a major cause of human illnesses, including septic shock and inflammatory bowel disease. In this grant application we propose to study the roles of MKP-1 in Gram-negative bacterial sepsis and colitis. These studies will uncover critical immune regulatory mechanisms, and may lead to novel strategies for the treatment of sepsis and inflammatory bowel disease.