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Infection and Immunity, March 2008, p. 1076-1082, Vol. 76, No. 3
0019-9567/08/$08.00+0     doi:10.1128/IAI.01098-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Fluid Secretion Caused by Aerolysin-Like Hemolysin of Aeromonas sobria in the Intestines Is Due to Stimulation of Production of Prostaglandin E₂ via Cyclooxygenase 2 by Intestinal Cells

Institute of Pharmacognosy, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro, Tokushima, Tokushima 770-8514,¹ Faculty of Pharmaceutical Sciences, Okayama University, Tsushima-naka, Okayama, Okayama 700-8530, Japan²

Received 8 August 2007/ Returned for modification 12 September 2007/ Accepted 4 December 2007

To clarify the mechanisms of diarrheal disease induced by Aeromonas sobria, we examined whether prostaglandin E₂ (PGE₂) was involved in the intestinal secretory action of A. sobria hemolysin by use of a mouse intestinal loop model. The amount of PGE₂ in jejunal fluid and the fluid accumulation ratio were directly related to the dose of hemolysin. The increase over time in the level of PGE₂ was similar to that of the accumulated fluid. In addition, hemolysin-induced fluid secretion and PGE₂ synthesis were inhibited by the selective cyclooxygenase 2 (COX-2) inhibitor NS-398 but not the COX-1 inhibitor SC-560. Western blot analysis revealed that hemolysin increased the COX-2 protein levels but reduced the COX-1 protein levels in mouse intestinal mucosa in vivo. These results suggest that PGE₂ functions as an important mediator of diarrhea caused by hemolysin and that PGE₂ is produced primarily through a COX-2-dependent mechanism. Subsequently, we examined the relationship between PGE₂, cyclic AMP (cAMP), and cystic fibrosis transmembrane conductance regulator (CFTR) Cl^– channels in mouse intestinal mucosa exposed to hemolysin. Hemolysin increased the levels of cAMP in the intestinal mucosa. NS-398 inhibited the increase in cAMP production, but SC-560 did not. In addition, H-89, a cAMP-dependent protein kinase A (PKA) inhibitor, and glibenclamide, a CFTR inhibitor, inhibited fluid accumulation. Taken together, these results indicate that hemolysin activates PGE₂ production via COX-2 and that PGE₂ stimulates cAMP production. cAMP then activates PKA, which in turn stimulates CFTR Cl^– channels and finally leads to fluid accumulation in the intestines.

Published ahead of print on 17 December 2007.

Editor: R. P. Morrison