Innate immune system modulated the expression of RANTES and the function of activated primary hepatic stellate cells

Background/Aims: Little is known how innate immune system modulate the expression of RANTES, thus progress the HCV-induced liver fibrosis. As Toll-like receptors (TLRs) and RIG-I like receptors (RLRs) are important in the regulation of innate and adaptive immune responses, we studied their role in the activation of HSC.

Methods: Primary isolated murine and human HSC were stimulated with TLR1–9 or RIG-I ligands for 24h. The expression of cytokines and C-C Motif Chemokine receptor 5 (CCR5) was estimated by quantitative RT-PCR while chemokine (C-C motif) ligand 5 (RANTES) production was measured by ELISA. Functional assays included inhibition reactions, proliferation, migration assays.

Results: Amongst all TLRs, Poly I:C/TLR3 was the most potent stimulus of RANTES for HSCs, which was additionally confirmed by TLR3-specific siRNA or chloroquine pretreatment in human HSC in vitro, and abrogated in TLR3-/- mice in vivo. RIG-I could also modulate the express of RANTES via TBK1/IKKε signal pathway. Migration of HSC was stimulated primarily through TLR3 which could be completely blocked by antibodies against RANTES. RANTES could stimulate the proliferation of HSCs and upregulate the expression of some TLR- and fibrogenisis-related genes.

Conclusions: We provided evidence that TLR- and RLR-agonists were able to induce the up-regulation of chemokine RANTES via different signal pathway, thus progress liver fibrosis. This sheds new light on the immunological role of HSC which may be of particular relevance for the pathogenesis of liver fibrosis.