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

Am J Physiol. 1996 Jun;270(6 Pt 1):C1581-7. doi: 10.1152/ajpcell.1996.270.6.C1581.


Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease that is characterized by selective destruction of insulin-secreting beta-cells. Cytokines have been implicated as effector molecules that participate in both islet inflammation and beta-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-1 beta (IL-1 beta), human recombinant tumor necrosis factor-alpha (TNF-alpha), and human recombinant interferon-gamma (IFN-gamma), induce the time-dependent formation of nitrite and prostaglandin E2 (PGE2) by human islets. The nitric oxide synthase inhibitor NG-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-1 beta, TNF-alpha, and IFN-gamma) 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-1 beta plus IFN-gamma-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).

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Arginine / analogs & derivatives
  • Arginine / pharmacology
  • Base Sequence
  • Benzoquinones
  • Cyclooxygenase Inhibitors / metabolism*
  • Cytokines / pharmacology*
  • Enzyme Induction
  • Enzyme Inhibitors / pharmacology
  • Genistein
  • Humans
  • Interferon-gamma / pharmacology
  • Interleukin-1 / pharmacology
  • Islets of Langerhans / metabolism*
  • Isoenzymes / antagonists & inhibitors*
  • Isoflavones / pharmacology
  • Lactams, Macrocyclic
  • Molecular Probes
  • Molecular Sequence Data
  • Nitric Oxide Synthase / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Quinones / pharmacology
  • Recombinant Proteins / pharmacology
  • Rifabutin / analogs & derivatives
  • Tumor Necrosis Factor-alpha / pharmacology
  • omega-N-Methylarginine


  • Benzoquinones
  • Cyclooxygenase Inhibitors
  • Cytokines
  • Enzyme Inhibitors
  • Interleukin-1
  • Isoenzymes
  • Isoflavones
  • Lactams, Macrocyclic
  • Molecular Probes
  • Quinones
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • Rifabutin
  • omega-N-Methylarginine
  • herbimycin
  • Interferon-gamma
  • Arginine
  • Genistein
  • Nitric Oxide Synthase
  • Protein-Tyrosine Kinases