Favored T helper 1 response in a mouse model of hepatosteatosis is associated with enhanced T cell-mediated hepatitis
Favored T helper 1 response in a mouse model of hepatosteatosis is associated with enhanced T cell-mediated hepatitis
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DOI：
10.1002/hep.21221
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发表时间：
2006-07-01
期刊：
影响因子：
13.5
通讯作者：
Wheeler, MD
中科院分区：
文献类型：
--
作者：
Kremer, M;Hines, IN;Wheeler, MD
脂肪性肝炎加重了急性炎症引起的肝损伤的严重程度。本研究的目的是检验慢性胆碱缺乏饮食引起的脂肪肝加重刀豆球蛋白A（conA）诱导的肝炎的假设，这主要是由T细胞facitatiated。在ConA给药前，雄性C57 BL/6小鼠喂食对照胆碱充足饮食（CSD）或胆碱缺乏饮食（CDD）6周。在ConA注射后3、9和24小时处死小鼠。在ConA暴露前，通过天冬氨酸氨基转移酶（AST）、丙氨酸氨基转移酶（ALT）、病理学和末端脱氧核苷酸转移酶介导的缺口末端标记（TUNEL）染色测量的小鼠肝损伤最小。然而，ConA诱导的肝损伤是显着更大的CD喂养的小鼠相比，对照喂养的小鼠。通过定量实时聚合酶链反应（PCR）评估肝脏细胞因子。辅助性T细胞（Th）1细胞因子肿瘤坏死因子α（INF-α）、白细胞介素12（IL-12）和干扰素γ的表达。与对照组小鼠相比，CD喂养小鼠中ConA后IFN-γ显著升高。CDD也增强ConA诱导的STAT 4激活，但不是STAT 6。值得注意的是，调节T细胞分化强烈转向一个占主导地位的Th 1型。T-bet是Th 1应答的调节因子，在喂食CD的小鼠中上调，而Th 2调节因子加塔-3在喂食CD的小鼠中在ConA后被显著抑制。此外，细胞因子信号转导抑制因子（SOCS）-1，SOCS-3和加塔-3（ROG）的抑制因子的表达有利于C1313喂养小鼠的主要Th 1细胞因子应答。总之，这些数据支持这一假设，即由CDD引起的脂肪肝与更严重的ConA诱导的肝炎，由于主要向Th 1反应的转变。
Steatohepatitis enhances the severity of liver injury caused by acute inflammation. The purpose of this study was to test the hypothesis that fatty liver due to chronic choline-deficient diet exacerbates concanavalinA (conA)-induced liver hepatitis, which is predominandy facititated by T cells. Male C57BL/6 mice were fed either control choline-sufficient diet (CSD) or choline-deficient diet (CDD) for 6 weeks before ConA administration. Mice were sacrificed 3, 9, and 24 hours after ConA injection. Liver injury measured by aspartate aminotransferase (AST), alanine aminotransferase (ALT), pathology, and terminal deoxynucleotidyl transferase-mediated nick-end labeling (TUNEL) staining was minimal in mice fed either diet before ConA exposure. However, ConA-induced liver injury was significantly greater in CDD-fed mice compared with control-fed mice. Liver cytokines were assessed by quantitative real-time polymerase chain reaction (PCR). The expression of T helper (Th) 1 cytokines tumor necrosis factor alpha (INF-alpha), interleukin 12 (IL-12), and interferon gamma. (IFN-gamma) were dramatically elevated after ConA in CDD-fed mice compared with control-fed mice. CDD also enhanced ConA-induced STAT4 activation, but not STAT6. Notably, regulators of T-cell differentiation were strongly shifted toward a predominant Th1 profile. T-bet, regulator of the Th1 response, was up-regulated in CDD-fed mice, whereas Th2 regulator GATA-3 was significantly suppressed in CDD-fed mice after ConA. Moreover, the expression of suppressor of cytokine signaling (SOCS)-1, SOCS-3, and repressor of GATA-3 (ROG) favored a predominant Th1 cytokine response in C1313-fed mice. In conclusion, these data support the hypothesis that hepatosteatosis caused by CDD is associated with more severe ConA-induced hepatitis due to a predominant shift toward Th1 response.