A CENTRAL ROLE FOR IL-1-BETA IN THE IN-VITRO AND IN-VIVO REGULATION OF HEPATIC INDUCIBLE NITRIC-OXIDE SYNTHASE IL-1-BETA INDUCES HEPATIC NITRIC-OXIDE SYNTHESIS
Da. Geller et al., A CENTRAL ROLE FOR IL-1-BETA IN THE IN-VITRO AND IN-VIVO REGULATION OF HEPATIC INDUCIBLE NITRIC-OXIDE SYNTHASE IL-1-BETA INDUCES HEPATIC NITRIC-OXIDE SYNTHESIS, The Journal of immunology, 155(10), 1995, pp. 4890-4898
We have previously demonstrated that high levels of inducible nitric o
xide synthase (iNOS) expression in hepatocytes required a combination
of LPS and TNF-alpha, IL-1 beta, and IFN-gamma. The need for such a co
mplex regulatory system seemed unwarranted based on the importance of
NO in the liver. Therefore, we investigated whether individual cytokin
es could induce NO synthesis in hepatocytes and characterized some of
the mechanisms involved. Rat hepatocytes were stimulated in vitro with
escalating doses of TNF-alpha, IL-1 beta, or IFN-gamma. Only IL-1 bet
a induced high levels of iNOS mRNA and corresponding NO2- + NO3- produ
ction, and dexamethasone and cycloheximide blocked a majority of this
response, Nuclear run-on experiments revealed that IL-1 beta upregulat
ed iNOS gene transcription. IL-1 receptor antagonist protein (IL-1ra)
competitively inhibited IL-1 beta-stimulated NO synthesis, implying ac
tivation through a cell-specific receptor. Rats injected with both LPS
and IL-1ra showed decreased hepatic iNOS mRNA and plasma NO2- + NO3-
compared with rats given LPS alone, indicating that IL-1 beta plays a
role in regulating iNOS expression within the liver in vivo during end
otoxemia. The soluble TNF receptor antagonist, PEG-(rsTNF-RI)(2), also
suppressed hepatic iNOS mRNA levels and plasma NO2- + NO3- increases,
supporting a role for this cytokine in LPS-induced iNOS expression. F
inally, IL-1 beta at high doses also induced iNOS mRNA and significant
NO2- + NO3- production in cultures of primary human hepatocytes. Thes
e data indicate an important role for IL-1 beta in the regulation of h
epatic NO synthesis.