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Abstract

Fibrosis in the liver is linked to the activation and proliferation of stellate cells. The injurious phenomenon that triggers this process must signal a phenotypic change by altering gene expression in stellate cells through the activation of transcription factors. Schnabl et al. explore a logical candidate system for regulation of transcription factors, namely the stress-activated kinases, JNK and p38, or an upstream kinase, TAKI, in cultured rat stellate cells that undergo time-dependent spontaneous activation. The use of dominant-negative TAKI or specific chemical inhibitors of JNK and p38 were used to develop a profile of responses controlled by these kinases. Interestingly, TAKI/JNK stimulated and p38 inhibited proliferation. Both were involved in ␣-smooth muscle actin expression only in early activation whereas collagen ␣-1(I) mRNA was decreased by JNK and increased by p38. Thus, quiescent and activated stellate cells respond differently to kinase inhibition, and JNK and p38 have opposite effects on proliferation and collagen gene expression. TAKI/JNK promotes proliferation and anti-differentiation whereas p38 is anti-proliferative and pro-differentiated. Future studies will be needed to exploit these differences in pharmacologic strategies to inhibit fibrosis in vivo. (See HEPATOL-OGY 2001;34:953-963.)