Escherichia coli STb toxin and prostaglandin production

Enterotoxigenic Escherichia coli cause diarrhoeal disease in humans and animals by elaboration of exotoxins which are divided into two groups based on thermal stability. The heat-labile (LT) and the heat-stable STa enterotoxins have been investigated in detail and much is known about their mechanisms of action and cellular targets. O n the other hand, studies to determine the mechanism of action of E. coli STb (heat-stable) toxin are still required to elucidate precisely the way(s) in which it acts on intestinal tissues. In spite of only rare studies conducted on the subject, some important facts have begun to emerge. A first study done by Greenberg et a f . (2), using heat-treated (65*C, 30 min) STb culture filtrates, investigated the central pathway(s) triggered by STb. They were the first to observe a stimulation (8-fold) of the intestinal secretion of prostaglandin E, (PGE,) in response to the administered toxin. STb had an early onset of action (30 min in the weaned pig loop assay) that resulted in intestinal PGE, secretion. At the same time, it was shown that STb stimulated secretion

through a cyclic-nucleotide-independent i Receptor stimulation could be coupled to pathway. This early report thus indicated the activation of phosphoinositide turnover that STb was acting differently from LT and i and/or activation of phospholipase A,. In the STa. Surprisingly, these observations were i gut, PGE, and serotonin promote intestinal only recently confirmed. In fact, Hitotsubashi secretion by apparently independent mechaet al. (S), using purified toxin, confirmed nisms, yet the release of serotonin and the that STb did not alter cyclic GMP nor cyclic i synthesis of PGE, may be coupled events. AMP levels in intestinal mucosal cells. As a i Overall, PGE, formation appears to arise result of STb action, the level of PGE, j through both serotonin-dependent and increased and prostaglandin inhibitors such i serotonin-independent pathways (3). As we as aspirin and indomethacin significantly 1 know that PGE, abolishes neutral sodium reduced the response to STb. Reduction of i chloride absorption and increases electrofluid secretion brought about by cyclo- f genic chloride ion secretion, it is quite oxygenase inhibitors has also been observed f puzzling to relate bicarbonate secretion and by us, using the rat loop assay as the animal f the absence of chloride observed in an Ussing model (J. D. Dubreuil & A. Letellier, unpub- f chamber in response to STb (8). lished observations). f From another point of view, being aware Later, Fujii et af. (1)established that che f that PGE, has a direct effect on smooth quantity of PGE, produced by intestinal cells f muscle cells, its production in response to was directly related to the quantity of toxin i STb could be responsible for the spontaneous administered to the mouse. Furthermore, the t motility observed in the mouse ileum. As quantity of PGE, also correlated with the i expected from this implication, papaverine, volume of fluid released into the intestinal i which is known to cause relaxation of smooth lumen. Since then, two other groups have also f muscle, had an inhibitory effect on STb (4). reported that PGE, and 5-hydroxytryptamine i In conclusion, although some secretion (serotonin),are released into the luminal fluid i mediators have been clearly shown to be as a result of STb action (3, 7). Peterson & f produced in response to STb toxin, the Whipp (7), when comparing the secretory f intricacy of their role in the production of effects of cholera toxin (CT),STa and STb in diarrhoea1 disease still demands some the pig intestinal loop model, observed that additional studies. f combining maximal doses of STa and STb i f and of C T and STb yielded additive fluid i; J. Daniel Dubreuil i accumulation. Together these experiments i f confirmed that the mechanism of action of i f STb enterotoxin is distinct from STa and CT, i although CT as well as STb stimulated the i Communications should be in the form release of PGE, and serotonin. of letters and should be brief and to the To summarize, results indicate that STb f point. A single small Table or Figure may i in vivo causes a dose-dependent increase in f be included, as may a limited number of i luminal PGE, and serotonin which are known f references (cited in the text by numbers, i secretagogues. As cyclooxygenase inhibitors f and listed in alphabetical order at the end diminish fluid secretion by STb, stimulation f of the letter). A short title (fewer than 50 of arachidonic acid metabolism in intestinal f characters) should be provided. i epithelial cells is clearly established. On the f i other hand, PGE, is known to stimulate i Approval for publication rests with the Editor-in-Chief, who reserves the intestinal adenylate cyclase, resulting in the right to edit letters and/or to make a 1 formation of CAMP (6).For STb, this rise in i i cyclic nucleotides that subsequently result f brief reply Other interested persons may 1 in chloride secretion has not been observed. also be invited to reply The Editors i Thus, serotonin could mediate the remaining of Microbiology do not necessarily agree with the views expressed in secretory effect observed for STb, In fact, at least part of PGE, seems to be produced in f Microbiohgy Comment. f response to serotonin receptor stimulation Contributions should be addressed to the as ketanserin, a receptor antagonist of sero- i Editor-in-Chief via the Editorial Office. ! tonin, reduced the level of PGE, observed. i



Microbiology 145, July 1999


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