Strain-specific differences in mouse hepatic wound healing are mediated by divergent T helper cytokine responses
Strain-specific differences in mouse hepatic wound healing are mediated by divergent T helper cytokine responses
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DOI：
10.1073/pnas.94.20.10663
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发表时间：
1997-09-30
影响因子：
11.1
通讯作者：
Rockey, DC
中科院分区：
文献类型：
--
作者：
Shi, ZD;Wakil, AE;Rockey, DC
肝纤维化代表肝脏对损伤的普遍反应，其特征是细胞外基质过度沉积。这一过程的细胞基础很复杂，涉及许多因素的相互作用，其中细胞因子是最突出的。我们已经确定了小鼠品系对损伤的不同纤维化反应，并利用这些差异来检查和对比纤维化过程中 T 辅助细胞 (Th) 衍生的细胞因子。用四氯化碳诱导肝损伤，定量纤维化，并测量 Th1/Th2 细胞因子 mRNA。 BALB/c 小鼠的肝损伤导致严重的纤维化，而 C57BL/6 小鼠的纤维化相对较轻。与野生型小鼠相比，T 细胞和 B 细胞缺陷的 BALB/c 和 C57BL/6 严重联合免疫缺陷 (SCID) 小鼠的纤维形成发生显着改变，这表明 Th 亚群的作用。纤维化 BALB/c 小鼠在受伤反应期间表现出 Th2 反应，而 C57BL/6 小鼠表现出 Th1 反应，表明肝纤维化受到不同 T 辅助细胞亚群的影响。此外，缺乏干扰素γ（默认Th2细胞因子途径）的小鼠比野生型动物表现出更明显的纤维化病变。最后，通过中和抗白细胞介素 4 或干扰素 γ 本身治疗将 Th2 反应转向 Th1 反应，改善了 BALB/c 小鼠的纤维化。这些数据支持免疫调节肝纤维化的作用，并表明 Th 细胞因子亚群可以调节对损伤的纤维化反应。
Hepatic fibrosis represents the generalized response of the liver to injury and is characterized by excessive deposition of extracellular matrix. The cellular basis of this process is complex and involves interplay of many factors, of which cytokines are prominent. We have identified divergent fibrosing responses to injury among mouse strains and taken advantage of these differences to examine and contrast T helper (Th)-derived cytokines during fibrogenesis. Liver injury was induced with carbon tetrachloride, fibrosis was quantitated, and Th1/Th2 cytokine mRNAs measured. Liver injury in BALB/c mice resulted in severe fibrosis, whereas C57BL/6 mice developed comparatively minimal fibrosis. Fibrogenesis was significantly modified in T and B cell-deficient BALB/c and C57BL/6 severe combined immunodeficient (SCID) mice compared with wild type counterparts, suggesting a role of Th subsets. Fibrogenic BALB/c mice exhibited a Th2 response during the wounding response, whereas C57BL/6 mice displayed a Th1 response, suggesting that hepatic fibrosis is influenced by different T helper subsets. Moreover, mice lacking interferon gamma, which default to the Th2 cytokine pathway, exhibited more pronounced fibrotic lesions than did wild-type animals. Finally, shifting of the Th2 response toward a Th1 response by treatment with neutralizing anti-interleukin 4 or with interferon gamma itself ameliorated fibrosis in BALB/c mice. These data support a role for immune modulation of hepatic fibrosis and suggest that Th cytokine subsets can modulate the fibrotic response to injury.