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Somatostatin Through Its Specific Receptor Inhibits Spontaneous and TNF-- and Bacteria-Induced IL-8 and IL-1ß Secretion from Intestinal Epithelial Cells¹

Yehuda Chowers^3,*, Liora Cahalon, Maor Lahav^*, Hagai Schor, Ruth Tal^*, Simon Bar-Meir^* and Mia Levite

^* Department of Gastroenterology, Chaim Sheba Medical Center, Tel-HaShomer, Israel; and Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel

Intestinal epithelial cells secrete proinflammatory cytokines and chemokines that are crucial in mucosal defense. However, this secretion must be tightly regulated, because uncontrolled secretion of proinflammatory mediators may lead to chronic inflammation and mucosal damage. The aim of this study was to determine whether somatostatin, secreted within the intestinal mucosa, regulates secretion of cytokines from intestinal epithelial cells. The spontaneous as well as TNF-- and Salmonella-induced secretion of IL-8 and IL-1ß derived from intestinal cell lines Caco-2 and HT-29 was measured after treatment with somatostatin or its synthetic analogue, octreotide. Somatostatin, at physiological nanomolar concentrations, markedly inhibited the spontaneous and TNF--induced secretion of IL-8 and IL-1ß. This inhibition was dose dependent, reaching >90% blockage at 3 nM. Furthermore, somatostatin completely abrogated the increased secretion of IL-8 and IL-1ß after invasion by Salmonella. Octreotide, which mainly stimulates somatostatin receptor subtypes 2 and 5, affected the secretion of IL-8 and IL-1ß similarly, and the somatostatin antagonist cyclo-somatostatin completely blocked the somatostatin- and octreotide-induced inhibitory effects. This inhibition was correlated to a reduction of the mRNA concentrations of IL-8 and IL-1ß. No effect was noted regarding cell viability. These results indicate that somatostatin, by directly interacting with its specific receptors that are expressed on intestinal epithelial cells, down-regulates proinflammatory mediator secretion by a mechanism involving the regulation of transcription. These findings suggest that somatostatin plays an active role in regulating the mucosal inflammatory response of intestinal epithelial cells after physiological and pathophysiological stimulations such as bacterial invasion.

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