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Gastroenterology. 2007 Sep;133(3):875-86. Epub 2007 Jul 3.

Inflammation and apoptosis in Clostridium difficile enteritis is mediated by PGE2 up-regulation of Fas ligand.

Author information

1
Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.

Abstract

BACKGROUND & AIMS:

Clostridium difficile toxin A causes acute inflammation and fluid secretion in experimental animals and patients with C difficile infection. We previously reported that toxin A increased cyclooxygenase-2/prostaglandin E(2) (PGE(2)) expression and apoptosis in human colonocytes. Here, we assessed the role of secreted PGE(2) in inflammation and enterocyte apoptosis in toxin A enteritis.

METHODS:

Effects of PGE(2) and PGE(2) blockade on toxin A-induced apoptosis of human colonocytes (NCM460) and of PGE(2) or toxin A on the Fas ligand (FasL) induction were analyzed by flow cytometry and Western blot. Functional activity of elevated FasL on colonocytes was assessed by coculture of colonocytes with Fas bearing Jurkat T cells. The involvement of PGE(2)-dependent Fas/FasL activation in toxin A enteritis was further assessed in either scid or FasL and Fas deficient mice.

RESULTS:

Inhibition of cyclooxygenase-2 by NS-398 and of PGE(2) using a blocking antibody markedly attenuated apoptosis in colonocytes exposed to toxin A. Enhanced expression and release of FasL followed PGE(2) or toxin A exposure in vivo and in vitro and also was significantly attenuated by treatment with NS-398 and PGE(2) blocking antibody. PGE(2) acting through an EP1 receptor activated nuclear factor-kappaB, which induced transcription of FasL. Toxin A enteritis was accompanied by increased cellular infiltration, fluid secretion, and mucosal damage in control mice, but this response was markedly reduced in both Fas(-/-) and FasL(-/-) mice.

CONCLUSIONS:

Toxin A enteritis involves release of PGE(2), which activates the Fas/FasL system, causing enterocyte apoptosis and inflammation.

PMID:
17854595
DOI:
10.1053/j.gastro.2007.06.063
[Indexed for MEDLINE]

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