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Am J Physiol Gastrointest Liver Physiol (June 26, 2003). doi:10.1152/ajpgi.00215.2003
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Submitted on May 9, 2003
Accepted on June 24, 2003

Human Hepatic Stellate Cells express CCR5 and RANTES to induce proliferation and migration

Robert F. Schwabe1, Ramon Bataller1, and David A. Brenner1*

1 Department of Medicine and Biochemistry & Biophysics, University of North Carolina, Chapel Hill, NC, USA

* To whom correspondence should be addressed. E-mail: dab2106{at}columbia.edu.

Activated hepatic stellate cells (HSCs) are the main producers of extracellular matrix in the fibrotic liver and are involved in the regulation of hepatic inflammation. The aim of this study was to characterize the role of regulated upon activation, normal T cell expressed and secreted (RANTES) in activated HSCs. RANTES mRNA and protein secretion were strongly induced after stimulating HSCs with TNF{alpha}, IL-1{beta} orCD40L. RANTES production was NF-{kappa}B dependent, since I{kappa}B superrepressor and dominant negative I{kappa}B kinase 2 almost completely blocked RANTES expression. NF-{kappa}B activation was sufficient to drive RANTES expression as demonstrated by the strong induction of RANTES in HSCs expressing NF-{kappa}B inducing kinase. The JNK/AP-1 pathway also contributed to RANTES expression as demonstrated by the blocking effects of the JNK inhibitor SP600125. HSCs responded to stimulation with recombinant human (rh) RANTES with an increase in intracellular calcium concentration and a rapid increase in free radical formation. Furthermore, rhRANTES induced ERK phosphorylation and ERK-dependent 3H-thymidine incorporation and HSC proliferation. Additionally, rhRANTES induced focal adhesion kinase phosphorylation and a substantial increase in HSC migration. HSCs functionally expressed chemokine receptor (CCR) 5, as shown by flow-cytometric analysis and RT-PCR and the inhibitory effects of a blocking CCR5 antibody on rhRANTES-induced ERK activation, proliferation and migration. Diphenylene iodonium and N-acetylcysteine inhibited rhRANTES-induced ERK activation and HSC proliferation indicating that NADPH oxidase-dependent production of reactive oxygen species was required. In conclusion, RANTES and CCR5 represent potential mediators of (1) HSC migration and proliferation and (2) a cross-talk between HSCs and leukocytes during fibrogenesis.




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