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J. Biol. Chem., Vol. 275, Issue 48, 37672-37678, December 1, 2000
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From the Institute of Pharmacology and Toxicology, University of
Lausanne, 27 Rue du Bugnon, 1005 Lausanne, Switzerland
Insulin-dependent diabetes
mellitus is an autoimmune disease in which pancreatic islet
Dominant Negative MyD88 Proteins Inhibit
Interleukin-1
/Interferon-
-mediated Induction of Nuclear
Factor 
B-dependent Nitrite Production and Apoptosis in
Cells*
,,
cells are destroyed by a combination of immunological and inflammatory
mechanisms. In particular, cytokine-induced production of nitric oxide
has been shown to correlate with cell apoptosis and/or inhibition
of insulin secretion. In the present study, we investigated whether the
interleukin (IL)-1 intracellular signal transduction pathway
could be blocked by overexpression of dominant negative forms of the
IL-1 receptor interacting protein MyD88. We show that
overexpression of the Toll domain or the lpr mutant of MyD88 in
Tc-Tet cells decreased nuclear factor 
B (NF-B)
activation upon IL-1 and IL-1/interferon (IFN)-
stimulation.
Inducible nitric oxide synthase mRNA accumulation and nitrite
production, which required the simultaneous presence of IL-1 and
IFN-, were also suppressed by ~70%, and these cells were more
resistant to cytokine-induced apoptosis as compared with parental
cells. The decrease in glucose-stimulated insulin secretion induced by
IL-1 and IFN- was however not prevented. This was because these
dysfunctions were induced by IFN- alone, which decreased cellular
insulin content and stimulated insulin exocytosis. These results
demonstrate that IL-1 is involved in inducible nitric oxide synthase
gene expression and induction of apoptosis in mouse cells but does
not contribute to impaired glucose-stimulated insulin secretion.
Furthermore, our data show that IL-1 cellular actions can be blocked
by expression of MyD88 dominant negative proteins and, finally, that
cytokine-induced cell secretory dysfunctions are due to the action
of IFN-.
*
This work was supported by Grants 31-46958.96 from the Swiss
National Science Foundation (to B. T.) and 31-49662.96 (to
E. F. B.). This work was also supported by Juvenile Diabetes
Foundation International Grant 4-1999-844 and Modex
Thérapeutiques.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Contributed equally to the work.
§
To whom correspondence should be addressed. Tel.: 021 692 53 90;
Fax: 021 692 53 55; E-mail: bthorens@ipharm.unil.ch.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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