Regulation of inducible nitric oxide synthase in hepatic sinusoidal
endothelial cells.
Rockey, Don C., and John J. Chung.
Liver Center Laboratory and the Department of Medicine, San
Francisco General Hospital, University of California, San Francisco,
California
APStracts 3:0033G, 1996.
Nitric oxide (NO) has many important physiologic effects, which depend
in part on its cellular source(s). In liver, NO is produced by all
major cell types, including hepatocytes, Kupffer, stellate and
sinusoidal endothelial cells (SECs). While endothelial cells have
been commonly associated with constitutive NO production, recent
evidence suggests that NO is inducible in this cell type. Here, we
investigated the regulation of inducible NO synthase (iNOS) in SECs.
Interferon [gamma] (IF[gamma]) and lipopolysaccharide (LPS) as
individual compounds, induced iNOS mRNA in SECs. Interleukin-1 [beta]
(IL-1[beta]) and tumor necrosis factor [alpha] (TNF[alpha]) had no
effect when used alone, but enhanced iNOS mRNA upregulation by
IF[gamma]. iNOS transcription after LPS was present only for 4 hours
after exposure, yet was more sustained after IF[gamma]/TNF[alpha].
LPS was unique in that it transiently induced iNOS mRNA, whereas
IF[gamma]/TNF[alpha] resulted in prolonged increases in iNOS mRNA.
Both LPS and IF[gamma]/TNF[alpha] caused prolonged elevation of
immunoreactive protein. However, when stimulated by LPS, iNOS
remained enzymatically active for only 24-48 hours. After IF[gamma]
or IF[gamma]/TNF[alpha], iNOS activity declined only moderately. LPS
added to IF[gamma] alone or IF[gamma]/TNF[alpha] did not result in
more rapid decay of iNOS enzymatic activity. These data indicate that
induction of iNOS by sinusoidal endothelial cells is prominent and
that it is regulated both transcriptionally and by its inactivation.
Such complex regulation of iNOS has important implications for NO
biology in liver disease.
Received 18 October 1995; accepted in final form 11 January 1996.
APS Manuscript Number G457-5.
Article publication pending Am. J. Physiol. (Gastrointest. Liver
Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 8 February 96