Heme Oxygenase-1 Alleviates Mouse Hepatic Failure through Suppression of Adaptive Immune Responses
Heme Oxygenase-1 Alleviates Mouse Hepatic Failure through Suppression of Adaptive Immune Responses
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Heme Oxygenase-1 通过抑制适应性免疫反应减轻小鼠肝衰竭
DOI：
10.1124/jpet.111.186551
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发表时间：
2012-01-01
影响因子：
3.5
通讯作者：
Zhang, Yanyun
中科院分区：
文献类型：
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作者：
Gu, Qiaoli;Wu, Qiong;Zhang, Yanyun
血红素氧合酶-1（HO-1）对伤害性刺激引起的肝损伤具有保护作用。HO-1的作用机制尚未完全了解。在本研究中，我们研究HO-1在由痤疮丙酸杆菌和脂多糖（LPS）诱导的暴发性肝衰竭模型中的作用。HO-1诱导剂钴原卟啉IX重复给药后，肝脏HO-1 mRNA和蛋白的表达增加。我们发现HO-1对痤疮丙酸杆菌/LPS诱导的小鼠急性肝损伤具有保护作用，并延长了小鼠的生存期。相反，HO-1抑制剂锌原卟啉IX的施用增加了由痤疮丙酸杆菌/LPS诱导的肝损伤。随后，为了研究HO-1在急性肝损伤模型中的潜在机制，我们仅用痤疮丙酸杆菌致敏小鼠。我们发现给予钴原卟啉IX后，树突状细胞（DC）中HO-1 mRNA和蛋白的表达增加。HO-1降低肝DCs上成熟标志物主要组织相容性复合物II和CD 80。成熟DC表达的CCR 7、CCL 2和CCL 22 mRNA的表达也降低。这些肝DC不能有效地刺激CD 4（+）T细胞的活化和增殖。因此，HO-1抑制肝脏浸润性CD 4（+）T细胞的活化、增殖和辅助性T细胞1极化，并减少血清丙氨酸氨基转移酶和促炎细胞因子（如干扰素-γ和肿瘤坏死因子-α）的产生。综上所述，我们的数据表明HO-1抑制痤疮丙酸杆菌/LPS诱导的暴发性肝衰竭，可能是通过抑制DC诱导的适应性反应。
Heme oxygenase-1 (HO-1) has protective effects on liver damage induced by noxious stimuli. The mechanism of action of HO-1 is not well understood. In the present study, we investigate the effect of HO-1 in a model of fulminant hepatic failure induced by Propionibacterium acnes and lipopolysaccharide (LPS). The expression of HO-1 mRNA and protein in the liver was increased after repeated administration of the HO-1 inducer cobalt protoporphyrin IX. We found that HO-1 protected mice from acute liver damage induced by P. acnes/LPS and prolonged survival. On the contrary, administration of the HO-1 inhibitor zinc protoporphyrin IX increased liver damage induced by P. acnes/LPS. Subsequently, to investigate the underlying mechanisms of HO-1 in the acute liver injury model, we primed mice with P. acnes only. We found that the expression of HO-1 mRNA and protein in dendritic cells (DCs) was increased after the administration of cobalt protoporphyrin IX. HO-1 decreased the mature markers major histocompatibility complex II and CD80 on liver DCs. The expression of CCR7, CCL2, and CCL22 mRNA, which are expressed by mature DCs, was also reduced. These liver DCs could not efficiently stimulate CD4(+) T cell activation and proliferation. Consequently, HO-1 inhibited the activation, proliferation, and T helper 1 polarization of liver-infiltrating CD4(+) T cells and reduced the production of serum alanine aminotransferase and proinflammatory cytokines such as interferon-gamma and tumor necrosis factor-alpha. Taken together, our data suggest that HO-1 alleviates P. acnes/LPS-induced fulminant hepatic failure, probably by inhibiting DC-induced adaptive responses.