High Mobility Group Box-1 Promotes the Proliferation and Migration of Hepatic Stellate Cells via TLR4-Dependent Signal Pathways of PI3K/Akt and JNK

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.

Low doses of ionizing radiation induce immune-stimulatory responses in isolated human primary monocytes

“…However, recently, the role of HMGB1 extended to include inflammation and necrosis (22). Activated monocytes and macrophages secrete HMGB1 and promote immune-stimulatory signaling (23). On the other hand, damaged cells 'passively' release HMGB1 into the extracellular environment (24), which could explain the dose-dependent response demonstrated in our data (Figs.…”

Emerging Role of High-Mobility Group Box 1 (HMGB1) in Liver Diseases

“…HMGB1 also has a synergistic effect with transforming growth factor β1 (TGF-β1) to stimulate expression of fibrogenic protein (for example, collagen α2 and α-SMA) in HSCs (72). HMGB1 promotes the proliferation/migration of HSCs and liver fibrosis partly via TLR4-MyD88 and the MAPK-NF-κB pathway ( Figure 4B) (72,73). These studies have demonstrated that HMGB1 and its profibrotic function may be effective targets to treat liver fibrosis.…”

Smoking Exposure Induces Human Lung Endothelial Cell Adaptation to Apoptotic Stress

“…In addition, knowing that HMGB1 conveys immunogenicity of the dying cell (38), the elevation of HMGB1 in lung endothelial cells challenged with ceramide may put forward the hypothesis that the ceramide-SPH-HMGB1 pathway participates in the autoimmune features of emphysema pathogenesis. Recent studies showed that HMGB1 promotes proliferation through Akt signaling pathway in hepatic stellate cells (39). Moreover, in mouse mesangial cells, HMGB1 increased the proliferation index, and the process was accompanied by down-regulation of p16…”