Basal Expression of Cyclooxygenase-2 and Nuclear Factor-Interleukin 6 are Dominant and Coordinately Regulated by Interleukin 1 in the Pancreatic Islet
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...
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Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 1998-02, Vol.95 (4), p.1788-1793 |
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Zusammenfassung: | 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 E2synthesis 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-κ B 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-κ B 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-κ B, 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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ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.95.4.1788 |