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Secretion1
* Department of Anatomy, Physiology, and Pharmacology, Auburn University, Auburn, AL 36849;
Institute of Human Virology, University of Maryland Biotechnology Institute, Baltimore, MD 21201;
Departments of Pathology and Laboratory Medicine, University of California, Irvine, CA 92697;
Scott-Ritchey Research Center,
¶ Department of Pathobiology,
|| Department of Biological Science, Auburn University, Auburn, AL 36849; and
# Division of Gastroenterology and Hepatology, University of Alabama at Birmingham, Birmingham, AL 35294
Impaired expression of 
-defensin antimicrobial peptides and overproduction of the proinflammatory cytokine IL-1
have been associated with inflammatory bowel disease. In this study, we examine the interactions between -defensins and IL-1 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 (-defensins) in the intestine, were more susceptible to dextran sulfate sodium-induced colitis. Furthermore, both baseline and dextran sulfate sodium-induced IL-1 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-1 production in defensin deficiency in vivo, we evaluated the effect of defensins on IL-1 posttranslational processing and release. It was found that -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-1 from LPS-activated monocytes, whereas TNF- expression and release were not affected. Unlike -defensins, human -defensins and mouse procryptdins do not have any effect on IL-1 processing and release. Thus, -defensins may play an important role in intestinal homeostasis by controlling the production of IL-1.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by a Career Development Award (to J.S.) from the Crohn’s and Colitis Foundation of America and an Auburn University Biogrant (to J.S.).
2 Address correspondence and reprint requests to Dr. Jishu Shi, Department of Anatomy, Physiology, and Pharmacology, Auburn University, 212 Greene Hall, Auburn, AL 36849. E-mail address: shijish{at}auburn.edu
3 Abbreviations used in this paper: HNP, human neutrophil peptide; MMP-7, matrix metalloproteinase 7; ICE, IL-1-converting enzyme; DSS, dextran sulfate sodium; Pen-Strep, penicillin-streptavidin; MLN, mesenteric lymph node; Crp, cryptdin; LDH, lactate dehydrogenase; HD, human defensin; PG-1, protegrin-1; hBD, human -defensin.
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