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标题：Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon
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作者：Laurent Peyrin-Biroulet ; Julia Beisner ; Guoxing Wang 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：19
页码：8772-8777
DOI：10.1073/pnas.0905745107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Crohn's disease (CD), a major form of human inflammatory bowel disease, is characterized by primary immunodeficiencies. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR{gamma}) is essential for intestinal homeostasis in response to both dietary- and microbiota-derived signals. Its role in host defense remains unknown, however. We show that PPAR{gamma} functions as an antimicrobial factor by maintaining constitutive epithelial expression of a subset of {beta}-defensin in the colon, which includes mDefB10 in mice and DEFB1 in humans. Colonic mucosa of Ppar{gamma} mutant animals shows defective killing of several major components of the intestinal microbiota, including Candida albicans, Bacteroides fragilis, Enterococcus faecalis, and Escherichia coli. Neutralization of the colicidal activity using an anti-mDefB10 blocking antibody was effective in a PPAR{gamma}-dependent manner. A functional promoter variant that is required for DEFB1 expression confers strong protection against Crohn's colitis and ileocolitis (odds ratio, 0.559; P = 0.018). Consistently, colonic involvement in CD is specifically linked to reduced expression of DEFB1 independent of inflammation. These findings support the development of PPAR{gamma}-targeting therapeutic and/or nutritional approaches to prevent colonic inflammation by restoring antimicrobial immunity in CD.
关键词：β-defensin 1 ; Crohn's disease ; microbiota ; nutrition ; PPAR-γ