Regulation of stellate cell proliferation by lipopolysaccharide: role of endogenous nitric oxide.
We studied the effect of lipopolysaccharide (LPS) on the proliferation of culture-stimulated rat stellate cells. DNA synthesis as determined by [3H]-thymidine incorporation was significantly suppressed by up to 52% compared with the control culture in the presence of LPS (> 5 ng/mL). Such an inhibitory effect of LPS was dramatically augmented in the presence of interferon-gamma (IFNgamma). Lipopolysaccharide alone or in combination with IFNgamma activated transcription factors AP-1 and NF-kappaB, and elicited nitric oxide (NO) production by stellate cells by inducing NO synthase. Inhibition of NO production by the addition of L-arginine antagonists to the culture, partially cancelled such an inhibitory effect of LPS and/or IFNgamma on DNA synthesis without affecting the activation of AP-1 and NF-kappaB and the NO synthase level. The cellular level of cyclic guanosine monophosphate (cGMP) increased in response to LPS and IFNgamma, and dibutyryl cGMP or 8-bromo-cGMP inhibited the incorporation of [3H]-thymidine in a dose-dependent manner. These results indicate that LPS is potent in modulating stellate cell proliferation by some NO- and cGMP-dependent mechanism.
Kawada
N
N
Department of Internal Medicine, Osaka City University Medical School, Abeno, Osaka, Japan. kawada-nori@mve.biglobe.ne.jp
Seki
S
S
Kuroki
T
T
Inoue
M
M
D000818:Animals; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D003995:Dibutyryl Cyclic GMP / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017208:Rats, Wistar; D018808:Transcription Factor AP-1 / Q000378:metabolism
D008070:Lipopolysaccharides; D016328:NF-kappa B; D018808:Transcription Factor AP-1; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D003995:Dibutyryl Cyclic GMP; D007371:Interferon-gamma; D004247:DNA; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D006152:Cyclic GMP