Roles of il-1 and tnf-[alpha] in endotoxin-induced activation of
nitric oxide synthase in cultured rat brain cells.
Romero, Luz I., Jeffrey B. Tatro, Jodie A. Field, and Seymour
Reichlin.
Division of Endocrinology, Diabetes, Metabolism and Molecular
Medicine, Tufts University School of Medicine and New England Medical
Center Hospitals, Boston, MA 02111
APStracts 2:0267R, 1995.
In astrocytes and microglia, bacterial lipopolysaccharide (LPS)
stimulates production and release of interleukin-1[beta] (IL
-1[beta]), tumor necrosis factor-[alpha] (TNF[alpha]) and nitric oxide
(NO). Although IL-1[beta] and TNF[alpha] are themselves capable of
inducing NO synthase (NOS) in glia, the specific factors mediating
LPS induction of NOS in brain have not been identified. To determine
whether LPS induction of NOS in brain cells is mediated by IL-1 or
TNF[alpha], acting alone or in concert, the effects of IL-1 receptor
antagonist (IL-1Ra) and of TNF soluble receptor (TNFsRp55), presented
individually and in combination, on LPS-induced NOS activity were
tested. In glia-enriched mixed primary cultures of neonatal rat
telencephalic cells, LPS (0.1-100 ng/ml), IL-1[beta] (0.01-10 nM),
and TNF[alpha] (0.1-100 nM) each concentration-dependently stimulated
accumulation of nitrite, an indicator of NO production. Induction of
nitrite accumulation by LPS and by IL1 was blocked by Nw-nitro-L
-arginine methyl ester (NAME) and Nw-monomethyl-L-arginine (LNMA),
indicating that it was mediated by nitric oxide synthase. TNF[alpha]
alone induced NO production weakly as compared with IL-1, but
combined submaximal concentrations of IL-1[beta] (1 nM) and
TNF[alpha] (10 nM) induced NOS synergistically. Furthermore, TNFsRp55
and IL-1Ra each produced a dose-dependent partial inhibition of the
NO response to LPS, and the effect of TNFsRp55 was equal to or
greater than that of IL-1Ra. TNFsRp55 and IL1-Ra in combination were
not significantly more effective than TNFsRp55 alone. The results
indicate that LPS induction of NOS activity in brain cells is
mediated in part by both IL-1[beta] and TNF[alpha].
Received 6 March 1995; accepted in final form 16 July 1995.
APS Manuscript Number R145-5.
Article publication pending Am. J. Physiol. (Regulatory Integrative
Comp. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 31 October 95