A novel role for defensins in intestinal homeostasis: regulation of IL-1beta secretion.
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.
Shi
Jishu
J
Department of Anatomy, Physiology, and Pharmacology, Auburn University, Auburn, AL 36849, USA. shijish@auburn.edu
Aono
Shelly
S
Lu
Wuyuan
W
Ouellette
Andre J
AJ
Hu
Xueyou
X
Ji
Yingbiao
Y
Wang
Lei
L
Lenz
Stephen
S
van Ginkel
Frederik W
FW
Liles
Mark
M
Dykstra
Christine
C
Morrison
Edward E
EE
Elson
Charles O
CO
D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000633:toxicity; D023082:Defensins / Q000235:genetics / Q000378:metabolism*; D016264:Dextran Sulfate / Q000633:toxicity; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D015212:Inflammatory Bowel Diseases / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D020783:Matrix Metalloproteinase 7 / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009000:Monocytes; D012323:RNA Processing, Post-Transcriptional; D017386:Sequence Homology, Amino Acid
D000998:Antiviral Agents; D023082:Defensins; D053583:Interleukin-1beta; D016264:Dextran Sulfate; D020783:Matrix Metalloproteinase 7