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 [³ H]-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-γ (IFNγ). Lipopolysaccharide alone or in combination with IFNγ activated transcription factors AP-1 and NF-κB, 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 IFNγ on DNA synthesis without affecting the activation of AP-1 and NF-κB and the NO synthase level. The cellular level of cyclic guanosine monophosphate (cGMP) increased in response to LPS and IFNγ, and dibutyryl cGMP or 8-bromo-cGMP inhibited the incorporation of [³ H]-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.