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
Date
06/01/1996Pubmed ID
8764139DOI
10.1152/ajpcell.1996.270.6.C1581Scopus ID
2-s2.0-0029745336 (requires institutional sign-in at Scopus site) 90 CitationsAbstract
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).
Author List
Corbett JA, Kwon G, Marino MH, Rodi CP, Sullivan PM, Turk J, McDaniel MLAuthor
John A. Corbett PhD Chair, Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
ArginineBase Sequence
Benzoquinones
Cyclooxygenase Inhibitors
Cytokines
Enzyme Induction
Enzyme Inhibitors
Genistein
Humans
Interferon-gamma
Interleukin-1
Islets of Langerhans
Isoenzymes
Isoflavones
Lactams, Macrocyclic
Molecular Probes
Molecular Sequence Data
Nitric Oxide Synthase
Protein-Tyrosine Kinases
Quinones
Recombinant Proteins
Rifabutin
Tumor Necrosis Factor-alpha
omega-N-Methylarginine