Tyrosine kinase inhibitors prevent cytokine-induced expression of
inos and cox-2 by human islets of langerhans.
Corbett, John A., Guim Kwon, Margaret H. Marino, Charles P. Rodi,
Patrick M. Sullivan, John Turk, and Michael L. McDaniel.
Department of Pathology, and Mass Spectrometry Resource, Division
of Endocrinology, Diabetes, and Metabolism, Division of Laboratory
Medicine, Department of Medicine, Washington University School of
Medicine, Saint Louis, MO 63110, Department of Cellular and Molecular
Biochemistry, Monsanto Corporate Research, Saint Louis, MO 63167,
Department of Protein Biochemistry, G. D. Searle, Saint Louis, MO
63167
APStracts 2:0451C, 1995.
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, IL-1[beta], TNF-[alpha], and
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 (NMMA) completely inhibits
cytokine-induced nitrite formation and attenuates PGE2 production by
human islets. 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 both by
reverse-transcriptase polymerase chain reaction (RT-PCR), and
Northern blot analysis. We further show that the tyrosine kinase
inhibitors genistein and herbimycin A prevent IL-1[beta] + 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 appear to require the activation of a tyrosine kinase(s).
Received 12 June 1995; accepted in final form 21 November 1995.
APS Manuscript Number C326-5.
Article publication pending Am. J. Physiol. (Cell Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 23 December 95