High mobility group box-1 promotes the proliferation and migration of hepatic stellate cells via TLR4-dependent signal pathways of PI3K/Akt and JNK.
High mobility group box-1 promotes the proliferation and migration of hepatic stellate cells via TLR4-dependent signal pathways of PI3K/Akt and JNK.
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DOI：
10.1371/journal.pone.0064373
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Jiang W
中科院分区：
文献类型：
--
作者：
Wang FP;Li L;Li J;Wang JY;Wang LY;Jiang W
肝星状细胞（hepatic stellate cells，HSC）的迁移是肝纤维化反应的关键，近年来发现高迁移率族蛋白1（High-mobility group box 1，HMGB 1）在肝纤维化过程中表达上调。然而，HMGB 1是否能够调节HSC的增殖和迁移以及所涉及的细胞内信号转导尚不清楚。本研究旨在观察HMGB 1对HSC增殖、迁移、促纤维化功能的影响，并探讨Toll样受体4（TLR 4）依赖的信号通路是否参与了HMGB 1的细胞内信号调节。采用改良的transwell小室系统模拟Disse间隙，检测人原代HSCs的迁移能力，并采用western blot检测相关信号因子的蛋白表达。MTT法检测细胞增殖活性，qRT-PCR法检测HSC促纤维化活性，ELISA法检测HSC促纤维化活性。重组人HMGB 1在趋化和触化刺激下均能显著促进HSC的迁移，尤其是后者。人TLR 4中和抗体可明显抑制HMGB 1诱导的HSC迁移。HMGB 1可增强JNK和PI 3 K/Akt的磷酸化，TLR 4中和抗体可抑制HMGB 1增强的JNK和PI 3 K/Akt的磷酸化及NF-κB的活化。JNK抑制剂（SP 600125）和PI 3 K抑制剂（LY 294002）可显著抑制HMGB 1诱导的HSC增殖和迁移，并降低HMGB 1诱导的相关胶原表达和促纤维化细胞因子的产生。HMGB 1在体外可显著促进HSC的迁移，且TLR 4依赖的JNK和PI 3 K/Akt信号通路参与了HMGB 1诱导HSC增殖、迁移和促纤维化的作用，提示HMGB 1可能是治疗肝纤维化的有效靶点。
The 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. Modified 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. HMGB1 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.
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