Dangi Anil, Huang Chao, Tandon Ashish, Stolz Donna, Wu Tong, Gandhi Chandrashekhar R
Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Surgery, University of Cincinnati, and Cincinnati VA Medical Center, Cincinnati, Ohio.
J Cell Physiol. 2016 Jan;231(1):94-105. doi: 10.1002/jcp.25055.
Bacterial lipopolysaccharide (LPS)-stimulated hepatic stellate cells (HSCs) produce many cytokines including IFNβ, TNFα, and IL6, strongly inhibit DNA synthesis, but induce apoptosis of a small number of hepatocytes. In vivo administration of LPS (up to 10 mg/mL) causes modest inflammation and weight loss in rats but not mortality. We determined whether LPS-stimulated HSCs instigate mechanisms of hepatocyte survival. Rats received 10 mg/kg LPS (i.p.) and determinations were made at 6 h. In vitro, HSCs were treated with 100 ng/mL LPS till 24 h. The medium was transferred to hepatocytes, and determinations were made at 0-12 h. Controls were HSC-conditioned medium or medium-containing LPS. LPS treatment of rats caused autophagy in hepatocytes, a physiological process for clearance of undesirable material including injured or damaged organelles. This was accompanied by activation of c-Jun NH2 terminal kinase (JNK) and apoptosis of ~4-5% of hepatocytes. In vitro, LPS-conditioned HSC medium (LPS/HSC) induced autophagy in hepatocytes but apoptosis of only ~10% of hepatocytes. While LPS/HSC stimulated activation of JNK (associated with cell death), it also activated NFkB and ERK1/2 (associated with cell survival). LPS-stimulated HSCs produced IFNβ, and LPS/HSC-induced autophagy in hepatocytes and their apoptosis were significantly inhibited by anti-IFNβ antibody. Blockade of autophagy, on the other hand, strongly augmented hepatocyte apoptosis. While LPS-stimulated HSCs cause apoptosis of a subpopulation of hepatocytes by producing IFNβ, they also induce cell survival mechanisms, which may be of critical importance in resistance to liver injury during endotoxemia.
细菌脂多糖（LPS）刺激的肝星状细胞（HSC）会产生多种细胞因子，包括IFNβ、TNFα和IL6，这些细胞因子会强烈抑制DNA合成，但仅诱导少数肝细胞凋亡。在大鼠体内给予LPS（高达10mg/mL）会引起适度的炎症反应和体重减轻，但不会导致死亡。我们确定了LPS刺激的HSC是否会引发肝细胞存活机制。给大鼠腹腔注射10mg/kg LPS，并在6小时后进行检测。在体外，用100ng/mL LPS处理HSC 24小时。将培养基转移至肝细胞，并在0 - 12小时后进行检测。对照组为HSC条件培养基或含LPS的培养基。给大鼠注射LPS会导致肝细胞自噬，这是一种清除包括受损细胞器在内的不良物质的生理过程。这伴随着c-Jun氨基末端激酶（JNK）的激活以及约4 - 5%的肝细胞凋亡。在体外，LPS条件的HSC培养基（LPS/HSC）可诱导肝细胞自噬，但仅约10%的肝细胞凋亡。虽然LPS/HSC刺激了与细胞死亡相关的JNK激活，但它也激活了与细胞存活相关的NFkB和ERK1/2。LPS刺激的HSC产生IFNβ，抗IFNβ抗体可显著抑制LPS/HSC诱导的肝细胞自噬及其凋亡。另一方面，自噬的阻断会强烈增强肝细胞凋亡。虽然LPS刺激的HSC通过产生IFNβ导致一部分肝细胞凋亡，但它们也诱导了细胞存活机制，这在内毒素血症期间对抵抗肝损伤可能至关重要。
