FIBRONECTIN AND CYTOKINES INCREASE JNK, ERK, AP-1 ACTIVITY, AND TRANSIN GENE-EXPRESSION IN RAT HEPATIC STELLATE CELLS

Cytokines, growth factors, and alterations in the extracellular matrix composition may play a role in maintaining hepatic stellate cells (HS C) in the activated state that is responsible for hepatic fibrogenesis . However, the signal transduction pathways that are stimulated by the se factors in HSC remain to be fully elucidated. Recent evidence indic ates that the mitogen-activated protein kinase (MAPK) family, includin g c-Jun NH2-terminal kinase (JNK) and extracellular signal-regulated k inase (ERK), plays an important role in the cellular response to stres s. The aims of this study were to investigate whether fibronectin (FN) or the inflammatory cytokines interleukin-1 alpha (IL-1 alpha) and tu mor necrosis factor-alpha (TNF-alpha) activate JNK, ERK, and AP-1 acti vity in HSC and induce the gene expression of the matrix metalloprotei nase transin. Treatment of HSC with FN resulted in an up to 4.5-fold i ncrease in ERK activity and a 2.1-fold increase in JNK activity. IL-1 alpha and TNF-alpha produced up to a fourfold increase in JNK activity and a twofold increase in ERK activity. We then compared the effects of FN, IL-1 alpha, and TNF-alpha on AP-1 activity and metalloproteinas e mRNA induction. All three compounds increased AP-1 binding and promo ter activity, and transin mRNA levels were increased 1.8-fold by FN, 2 .2-fold by IL-1 alpha, and 2.8-fold by TNF-alpha. Therefore, FN and in flammatory cytokines increase MAPK activity, stimulate AP-1 activity, and increase transin gene expression in HSC. Signal transduction pathw ays involving the MAPK family may play an important role in the regula tion of matrix metalloproteinase expression by cytokines and FN in HSC .