Basal expression of cyclooxygenase-2 and nuclear factor-interleukin 6 are dominant and coordinately regulated by interleukin 1 in the pancreatic islet
Animals; CCAAT-Enhancer-Binding Proteins; Cells, Cultured; Cricetinae; Cyclooxygenase 1; Cyclooxygenase 2; DNA-Binding Proteins; Dinoprostone; Gene Expression Regulation, Enzymologic; Humans; Interleukin-1; Islets of Langerhans; Isoenzymes; Membrane Proteins; Mutagenesis; NF-kappa B; Nuclear Proteins; Promoter Regions (Genetics); Prostaglandin-Endoperoxide Synthases; RNA, Messenger; Time Factors
Life Sciences | Medicine and Health Sciences
The enzyme cyclooxygenase (COX)-1 is constitutive whereas COX-2 is regulated in virtually all tissues. To assess whether this dogma holds true in the pancreatic islet, we examined basal and interleukin (IL)-1-regulated expression of COX-2 in HIT-T15 cells, Syrian hamster and human islets, and other Syrian hamster tissues. We found that COX-2, and not COX-1, gene expression is dominant in pancreatic islet tissue under both basal and IL-1-stimulated conditions. Control tissues (liver, spleen, and kidney) showed the expected predominance of COX-1 gene expression. Basal and IL-1-stimulated prostaglandin E2 synthesis were blocked by a specific COX-2 inhibitor. IL-1 stimulation had a biphasic effect on COX-2 mRNA levels with an initial mild increase at 2-4 hr followed by a more dramatic decrease below basal level by 24 hr. The IL-1-induced increase in COX-2 mRNA levels was accompanied by a parallel increase in NF-kappaB binding to COX-2 promoter elements. The subsequent decrease in COX-2 mRNA levels was accompanied by a parallel decrease in NF-IL-6 binding activity and COX-2 promoter activity. Specific mutation of the NF-IL-6 binding motif within the COX-2 promoter reduced basal promoter activity by 50% whereas mutation of the NF-kappaB motif had no effect. These studies provide documentation of NF-IL-6 in the pancreatic islet and that COX-2, rather than COX-1, is dominantly expressed. They suggest coordinate regulation by IL-1 of COX-2 mRNA, NF-kappaB, and NF-IL-6 and raise the issue of whether intrinsically high levels of COX-2 gene expression predisposes the normal islet for microenvironmentally induced overproduction of islet prostaglandin E2.
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Citation: Proc Natl Acad Sci U S A. 1998 Feb 17;95(4):1788-93.
Proceedings of the National Academy of Sciences of the United States of America
Sorli, Christopher H.; Zhang, Hui-Jian; Armstrong, Michael B.; Rajotte, Ray V.; Maclouf, Jacques A.; and Robertson, R. Paul, "Basal expression of cyclooxygenase-2 and nuclear factor-interleukin 6 are dominant and coordinately regulated by interleukin 1 in the pancreatic islet" (1998). Open Access Articles. 1793.