Cyclooxygenase-2, not microsomal prostaglandin E synthase-1, is the mechanism for interleukin-1-β-induced prostaglandin E2 production and inhibition of insulin secretion in pancreatic islets

Susan Parazzoli, Jamie S. Harmon, Sara N. Vallerie, Tao Zhang, Huarong Zhou, R. Paul Robertson

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Arachidonic acid is converted to prostaglandin E2 (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 PGE2 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 PGE2 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 ofWTand 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 PGE2 production and subsequent inhibition of insulin secretion.

Original languageEnglish (US)
Pages (from-to)32246-32253
Number of pages8
JournalJournal of Biological Chemistry
Volume287
Issue number38
DOIs
StatePublished - Sep 14 2012

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