Abstract
BackgroundThe migration of hepatic stellate cells (HSCs) is essential to the hepatic fibrotic response, and recently High-mobility group box 1 (HMGB1) has been shown up-regulated during liver fibrosis. Nevertheless, whether HMGB1 can modulate the proliferation and migration of HSCs is poorly understood, as well as the involved intracellular signaling. In this study, we examined the effect of HMGB1 on proliferation, migration, pro-fibrotic function of HSCs and investigated whether toll-like family of receptor 4 (TLR4) dependent signal pathway is involved in the intracellular signaling regulation.Methodology/Principal FindingsModified transwell chamber system to mimic the space of Disse was used to evaluate the migration of human primary HSCs, and the protein expressions of related signal factors were evaluated by western blot. Cell proliferation was analyzed by MTT assay, the pro-fibrotic functions of HSCs by qRT-PCR and ELISA respectively. Recombinant human HMGB1 could significantly promote migration of HSCs under both haptotactic and chemotactic stimulation, especially the latter. Human TLR4 neutralizing antibody could markedly inhibit HMGB1-induced migration of HSCs. HMGB1 could enhance the phosphorylation of JNK and PI3K/Akt, and TLR4 neutralizing antibody inhibited HMGB1-enhanced phosphorylation of JNK and PI3K/Akt and activation of NF-κB. JNK inhibitor (SP600125) and PI3K inhibitor (LY 294002) significantly inhibited HMGB1-induced proliferation and migration of HSCs, and also reduced HMGB1-enhanced related collagen expressions and pro-fibrotic cytokines production.Conclusions/SignificanceHMGB1 could significantly enhance migration of HSCs in vitro, and TLR4-dependent JNK and PI3K/Akt signal pathways are involved in the HMGB1-induced proliferation, migration and pro-fibrotic effects of HSCs, which indicates HMGB1 might be an effective target to treat liver fibrosis.
Highlights
Liver fibrosis caused by chronic liver diseases affects millions of people worldwide
To examine the effects of Highmobility group box 1 (HMGB1) on the migration of primary human hepatic stellate cells (HSCs), we employed the modified Boyden Chamber system mimicing the space of Disse in vivo
The results showed that preblockage of toll-like family of receptor 4 (TLR4) significantly inhibited HSCs proliferation and migration compared with those stimulated only with HMGB1, which was consistent with the outcomes of Jun N-terminal kinase (JNK) and phosphoinositide 3-kinase (PI3K)/Akt inhibitor experiments (Figure 4A & 4C)
Summary
Liver fibrosis caused by chronic liver diseases affects millions of people worldwide. Quiescent HSCs are mainly involved in Vitamin A metabolism, but they may proliferate, produce ECM and even migrate following activation [3]. The motility of HSCs can be influenced by changes in their microenvironment, including extracellular matrix and growth factors [4]. The migration of hepatic stellate cells (HSCs) is essential to the hepatic fibrotic response, and recently Highmobility group box 1 (HMGB1) has been shown up-regulated during liver fibrosis. Whether HMGB1 can modulate the proliferation and migration of HSCs is poorly understood, as well as the involved intracellular signaling. We examined the effect of HMGB1 on proliferation, migration, pro-fibrotic function of HSCs and investigated whether toll-like family of receptor 4 (TLR4) dependent signal pathway is involved in the intracellular signaling regulation
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