Tyrosine kinase inhibitors prevent cytokine-induced expression of iNOS and COX-2 by human islets

John A. Corbett, Guim Kwon, Margaret H. Marino, Charles P. Rodi, Patrick M. Sullivan, John Turk, Michael L. McDaniel

Research output: Contribution to journalArticlepeer-review

90 Scopus citations

Abstract

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease that is characterized by selective destruction of insulin-secreting β-cells. Cytokines have been implicated as effector molecules that participate in both islet inflammation and β-cell destruction during the development of IDDM. In this study, the effects of cytokines on the expression of inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (COX-2) by human islets were examined. In combination, the cytokines, human recombinant interleukin- 1β (IL-1β), human recombinant tumor necrosis factor-α (TNF-α), and human recombinant interferon-γ (IFN-γ), induce the time-dependent formation of nitrite and prostaglandin E2 (PGE2) by human islets. The nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA) completely inhibits cytokine-induced nitrite formation and attenuates PGE2 production by human islets. L-NMMA does not inhibit cytokine-induced expression of COX-2 by human islets, suggesting that nitric oxide may directly activate cyclooxygenase, an effect that has been previously demonstrated for isolated rat islets. This combination of cytokines (IL-1β, TNF-α, and IFN-γ) also induces the expression of iNOS mRNA by human islets as demonstrated by both reverse transcriptase-polymerase chain reaction and Northern blot analysis. We further show that the tyrosine kinase inhibitors genistein and herbimycin A prevent IL-1β plus IFN-γ-induced expression of COX-2 and iNOS and the production of PGE2 and nitric oxide by human islets. These results demonstrate that cytokines induce the expression of iNOS and COX-2 by human islets and that cytokine-induced expression of both COX-2 and iNOS by human islets appears to require the activation of a tyrosine kinase(s).

Original languageEnglish
Pages (from-to)C1581-C1587
JournalAmerican Journal of Physiology - Cell Physiology
Volume270
Issue number6 39-6
DOIs
StatePublished - Jun 1996

Keywords

  • cyclooxygenase
  • diabetes
  • inducible cyclooxygenase
  • inducible nitric oxide synthase
  • islets of Langerhans
  • nitric oxide

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