Abnormal Paneth cell granule dissolution and compromised resistance to bacterial colonization in the intestine of CF mice

被引:55
作者
Clarke, LL
Gawenis, LR
Bradford, EM
Judd, LM
Boyle, KT
Simpson, JE
Shull, GE
Tanabe, H
Ouellette, AJ
Franklin, CL
Walker, NM
机构
[1] Univ Missouri, Dalton Cardiovasc Res Ctr, Columbia, MO 65211 USA
[2] Univ Missouri, Dept Biomed Sci, Columbia, MO 65211 USA
[3] Univ Missouri, Dept Vet Pathol, Columbia, MO 65211 USA
[4] Univ Cincinnati, Dept Mol Genet Biochem & Microbiol, Cincinnati, OH 45267 USA
[5] Univ Calif Irvine, Dept Pathol, Irvine, CA 92697 USA
[6] Univ Calif Irvine, Dept Microbiol & Mol Genet, Irvine, CA 92697 USA
来源
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY | 2004年 / 286卷 / 06期
关键词
defensin; cryptdins; innate immunity; intestinal infection; inflammation;
D O I
10.1152/ajpgi.00393.2003
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
Paneth cells of intestinal crypts contribute to host defense by producing antimicrobial peptides that are packaged as granules for secretion into the crypt lumen. Here, we provide evidence using light and electron microscopy that postsecretory Paneth cell granules undergo limited dissolution and accumulate within the intestinal crypts of cystic fibrosis (CF) mice. On the basis of this finding, we evaluated bacterial colonization and expression of two major constituents of Paneth cells, i.e., alpha-defensins (cryptdins) and lysozyme, in CF murine intestine. Paneth cell granules accumulated in intestinal crypt lumens in both untreated CF mice with impending intestinal obstruction and in CF mice treated with an osmotic laxative that prevented overt clinical symptoms and mucus accretion. Ultrastructure studies indicated little change in granule morphology within mucus casts, whereas granules in laxative-treated mice appear to undergo limited dissolution. Protein extracts from CF intestine had increased levels of processed cryptdins compared with those from wild-type (WT) littermates. Nonetheless, colonization with aerobic bacteria species was not diminished in the CF intestine and oral challenge with a cryptdin-sensitive enteric pathogen, Salmonella typhimurium, resulted in greater colonization of CF compared with WT intestine. Modest downregulation of cryptdin and lysozyme mRNA in CF intestine was shown by microarray analysis, real-time quantitative PCR, and Northern blot analysis. Based on these findings, we conclude that antimicrobial peptide activity in CF mouse intestine is compromised by inadequate dissolution of Paneth cell granules within the crypt lumens.
引用
收藏
页码:G1050 / G1058
页数:9
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