A novel role for defensins in intestinal homeostasis: regulation of IL-1beta secretion.

Abstract	Impaired expression of alpha-defensin antimicrobial peptides and overproduction of the proinflammatory cytokine IL-1beta have been associated with inflammatory bowel disease. In this study, we examine the interactions between alpha-defensins and IL-1beta and the role of defensin deficiency in the pathogenesis of inflammatory bowel disease. It was found that matrix metalloproteinase-7-deficient (MMP-7(-/-)) mice, which produce procryptdins but not mature cryptdins (alpha-defensins) in the intestine, were more susceptible to dextran sulfate sodium-induced colitis. Furthermore, both baseline and dextran sulfate sodium-induced IL-1beta production in the intestine were significantly up-regulated in MMP-7(-/-) mice compared with that in control C57BL/6 mice. To elucidate the molecular mechanism for the increased IL-1beta production in defensin deficiency in vivo, we evaluated the effect of defensins on IL-1beta posttranslational processing and release. It was found that alpha-defensins, including mouse Paneth cell defensins cryptdin-3 and cryptdin-4, human neutrophil defensin HNP-1, and human Paneth cell defensin HD-5, blocked the release of IL-1beta from LPS-activated monocytes, whereas TNF-alpha expression and release were not affected. Unlike alpha-defensins, human beta-defensins and mouse procryptdins do not have any effect on IL-1beta processing and release. Thus, alpha-defensins may play an important role in intestinal homeostasis by controlling the production of IL-1beta.
Authors	Jishu Shi, Shelly Aono, Wuyuan Lu, Andre J Ouellette, Xueyou Hu, Yingbiao Ji, Lei Wang, Stephen Lenz, Frederik W van Ginkel, Mark Liles, Christine Dykstra, Edward E Morrison, Charles O Elson
Journal	Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 179 Issue 2 Pg. 1245-53 (Jul 15 2007) ISSN: 0022-1767 [Print] United States
PMID	17617617 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antiviral Agents Defensins Interleukin-1beta Dextran Sulfate Matrix Metalloproteinase 7
Topics	Amino Acid Sequence Animals Antiviral Agents (toxicity) Defensins (genetics, metabolism) Dextran Sulfate (toxicity) Homeostasis (physiology) Humans Immunoprecipitation Inflammatory Bowel Diseases (metabolism) Interleukin-1beta (metabolism) Intestinal Mucosa (metabolism) Matrix Metalloproteinase 7 (deficiency) Mice Mice, Inbred C57BL Molecular Sequence Data Monocytes RNA Processing, Post-Transcriptional Sequence Homology, Amino Acid

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