Inhibition of interleukin-1beta-induced COX-2 and EP3 gene expression by sodium salicylate enhances pancreatic islet beta-cell function.
Previous work has suggested that functional interrelationships may exist between inhibition of insulin secretion by interleukin (IL)-1beta and the endogenous synthesis of prostaglandin E(2) (PGE(2)) in the pancreatic islet. These studies were performed to ascertain the relative abundance of E prostaglandin (EP) receptor mRNAs in tissues that are major targets, or major degradative sites, of insulin; to identify which EP receptor type mediates PGE(2) inhibition of insulin secretion in pancreatic islets; and to examine possible sites of action through which sodium salicylate might affect IL-1beta/PGE(2) interactions. Real-time fluorescence-based RT-PCR indicated that EP3 is the most abundant EP receptor type in islets, liver, kidney, and epididymal fat. EP3 mRNA is the least, whereas EP2 mRNA is the most, abundant type in skeletal muscle. Misoprostol, an EP3 agonist, inhibited glucose-induced insulin secretion from islets, an event that was prevented by preincubation with pertussis toxin, by decreasing cAMP. Electromobility shift assays demonstrated that sodium salicylate inhibits IL-1beta-induced nuclear factor-kappaB (NF-kappaB) activation. Sodium salicylate also prevented IL-1beta from inducing EP3 and cyclooxygenase (COX)-2 gene expression in islets and thereby prevented IL-1beta from inhibiting glucose-induced insulin secretion. These findings indicate that the sites of action through which sodium salicylate inhibits these negative effects of IL-1beta on beta-cell function include activation of NF-kappaB as well as generation of PGE(2) by COX-2.
Tran
Phuong Oanh T
PO
Pacific Northwest Research Institute and Department of Medicine, University of Washington, Seattle, Washington 98122, USA.
Gleason
Catherine E
CE
Robertson
R Paul
RP
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D004822:Epididymis; D015870:Gene Expression / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007375:Interleukin-1 / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology*; D007527:Isoenzymes / Q000235:genetics*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D018482:Muscle, Skeletal / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D051381:Rats; D017208:Rats, Wistar; D018078:Receptors, Prostaglandin E / Q000235:genetics*; D058308:Receptors, Prostaglandin E, EP3 Subtype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012980:Sodium Salicylate / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007328:Insulin; D007375:Interleukin-1; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; C545647:PTGER3 protein, human; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D005947:Glucose; D015232:Dinoprostone; D012980:Sodium Salicylate