Key Laboratory of Chongqing Hepatobiliary Surgery Key Laboratory of Molecular Biology for Infectious Diseases, People's Republic of China Ministry of Education, Institute for Viral Hepatitis, Chongqing Medical University, Chongqing, China.
Hepatol Res. 2011 Oct;41(10):989-99. doi: 10.1111/j.1872-034X.2011.00852.x.
Glucocorticoid-induced tumor necrosis factor receptor ligand (GITRL) plays pro-inflammatory roles in immune response. Thus, our aim was to assess if dexamethasone attenuates lipopolysaccharide (LPS)-induced liver injury by affecting GITRL in Kupffer cells (KC).
A BALB/c mouse model of liver injury was established by i.p. injecting with LPS (10 mg/kg) co-treated with or without dexamethasone (3 mg/kg). Blood and liver samples were obtained for analysis of liver morphology, GITRL expression, hepatocellular function and cytokine levels at 24 h after injection. KC were isolated and challenged by LPS (1 µg/mL), with or without dexamethasone (10 µM) co-treatment, or with GITRL siRNA pre-transfection. The GITRL expression and cytokine levels were assayed at 24 h after challenge.
Dexamethasone treatment significantly improved the survival rate of endotoxemic mice (P < 0.05), whereas serum alanine aminotransferase, aspartate aminotransferase, tumor necrosis factor (TNF)-α, interleukin (IL)-6 and γ-interferon levels were significantly decreased (P < 0.05, respectively). Concurrently, LPS-induced hepatic tissue injury was attenuated as indicated by morphological analysis; and expression of GITRL in liver tissue and KC was downregulated (P < 0.05). Consistent with these in vivo experiments, inhibited expression of GITRL, TNF-α and IL-6 caused by dexamethasone treatment were also observed in LPS-stimulated KC. The GITRL, TNF-α and IL-6 expression was also significantly inhibited by GITRL gene silencing.
The TNF-α and IL-6 expression of LPS-stimulated KC was inhibited by GITRL gene silencing. Dexamethasone attenuates LPS-induced liver injury, at least proportionately, by downregulating GITRL in KC.
糖皮质激素诱导的肿瘤坏死因子受体配体（GITRL）在免疫反应中发挥促炎作用。因此，我们的目的是评估地塞米松是否通过影响枯否细胞（KC）中的 GITRL 来减轻脂多糖（LPS）诱导的肝损伤。
通过腹腔注射 LPS（10mg/kg）建立 BALB/c 小鼠肝损伤模型，并用或不用地塞米松（3mg/kg）共同处理。在注射后 24 小时，采集血液和肝脏样本，用于分析肝脏形态、GITRL 表达、肝细胞功能和细胞因子水平。分离并通过 LPS（1μg/mL）刺激 KC，并用或不用地塞米松（10μM）共同处理，或用 GITRL siRNA 预先转染。在刺激后 24 小时，测定 GITRL 表达和细胞因子水平。
地塞米松治疗显著提高了内毒素血症小鼠的存活率（P<0.05），而血清丙氨酸氨基转移酶、天冬氨酸氨基转移酶、肿瘤坏死因子（TNF）-α、白细胞介素（IL）-6 和γ-干扰素水平显著降低（P<0.05，分别）。同时，形态学分析表明 LPS 诱导的肝组织损伤减轻；并且肝组织和 KC 中的 GITRL 表达下调（P<0.05）。与这些体内实验一致，在 LPS 刺激的 KC 中也观察到地塞米松治疗抑制 GITRL、TNF-α 和 IL-6 的表达。GITRL 基因沉默也显著抑制了 GITRL、TNF-α 和 IL-6 的表达。
GITRL 基因沉默抑制 LPS 刺激的 KC 中 TNF-α 和 IL-6 的表达。地塞米松通过下调 KC 中的 GITRL 来减轻 LPS 诱导的肝损伤，至少部分是这样。
