CYTOKINES INDUCE NF-KAPPA-B IN ACTIVATED BUT NOT IN QUIESCENT RAT HEPATIC STELLATE CELLS

The hepatic stellate cell (HSC), after a fibrogenic stimulus, is trans formed from a quiescent to an activated phenotype, including the induc tion of responsiveness to a variety of agonists. We investigated the a ctivation of nuclear factor-KB (NF-kappa B) and the expression of the NF-kappa B-responsive genes intercellular adhesion molecule 1 (ICAM-1) and macrophage inflammatory protein-2 (MIP-2) in freshly isolated and culture-activated HSC by tumor necrosis factor-alpha (TNF-alpha) or i nterleukin-1 beta. Inhibitor-kappa B was rapidly (<15 min) degraded, a nd NF-kappa B activity was induced in culture-activated but not in fre shly isolated HSC after cytokine stimulation. After 30 min of stimulat ion, immunofluorescence revealed that the NF-kappa B p65 subunit was p redominantly found in the nuclei of activated HSC compared with the cy toplasmic localization in unstimulated cells. No nuclear translocation appeared in freshly isolated HSC after stimulation, despite the prese nce of functional TNF-alpha receptors. NF-kappa B nuclear translocatio n appeared first partially after 4-5 days and completely after 9 days in culture. Consistent with this time course TNF-alpha induced the mRN A of the NF-kappa B-dependent genes ICAM-1 and MIP-2 in activated but not in quiescent HSC. Therefore, cytokines induce NF-kappa B activity and ICAM-1 and MIP-2 mRNAs in activated but not in quiescent HSC, thro ugh a postreceptor mechanism of regulation.