title: Cyclooxygenase-2, not microsomal prostaglandin E synthase-1, is the mechanism for interleukin-1β-induced prostaglandin E2 production and inhibition of insulin secretion in pancreatic islets.
abstract: Arachidonic acid is converted to prostaglandin E(2) (PGE(2)) by a sequential enzymatic reaction performed by two isoenzyme groups, cyclooxygenases (COX-1 and COX-2) and terminal prostaglandin E synthases (cPGES, mPGES-1, and mPGES-2). mPGES-1 is widely considered to be the final enzyme regulating COX-2-dependent PGE(2) synthesis. These generalizations have been based in most part on experiments utilizing gene expression analyses of cell lines and tumor tissue. To assess the relevance of these generalizations to a native mammalian tissue, we used isolated human and rodent pancreatic islets to examine interleukin (IL)-1β-induced PGE(2) production, because PGE(2) has been shown to mediate IL-1β inhibition of islet function. Rat islets constitutively expressed mRNAs of COX-1, COX-2, cPGES, and mPGES-1. As expected, IL-1β increased mRNA levels for COX-2 and mPGES-1, but not for COX-1 or cPGES. Basal protein levels of COX-1, cPGES, and mPGES-2 were readily detected in whole cell extracts but were not regulated by IL-1β. IL-1β increased protein levels of COX-2, but unexpectedly mPGES-1 protein levels were low and unaffected. In microsomal extracts, mPGES-1 protein was barely detectable in rat islets but clearly present in human islets; however, in neither case did IL-1β increase mPGES-1 protein levels. To further assess the importance of mPGES-1 to IL-1β regulation of an islet physiologic response, glucose-stimulated insulin secretion was examined in isolated islets of WT and mPGES-1-deficient mice. IL-1β inhibited glucose-stimulated insulin secretion equally in both WT and mPGES-1(-/-) islets, indicating that COX-2, not mPGES-1, mediates IL-1β-induced PGE(2) production and subsequent inhibition of insulin secretion.
authors: Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington, Seattle, Washington 98122, USA.
authors: Susan
authors: S
authors: Parazzoli
authors: Jamie S
authors: JS
authors: Harmon
authors: Sara N
authors: SN
authors: Vallerie
authors: Tao
authors: T
authors: Zhang
authors: Huarong
authors: H
authors: Zhou
authors: R Paul
authors: RP
authors: Robertson
mesh_terms: D000818:Animals; D051546:Cyclooxygenase 2 / Q000378:metabolism / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D053583:Interleukin-1beta / Q000378:metabolism*; D019746:Intramolecular Oxidoreductases / Q000737:chemistry*; D007515:Islets of Langerhans / Q000166:cytology* / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008861:Microsomes / Q000201:enzymology*; D008954:Models, Biological; D000071876:Prostaglandin-E Synthases; D011453:Prostaglandins / Q000378:metabolism; D051381:Rats
chemical_list: D007328:Insulin; D053583:Interleukin-1beta; D011453:Prostaglandins; D051546:Cyclooxygenase 2; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; C000605863:PTGES2 protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; C000605866:Ptges2 protein, mouse