Th1 cytokine-induced downregulation of PPARγ in human biliary cells relates to cholangitis in primary biliary cirrhosis
Th1 cytokine-induced downregulation of PPARγ in human biliary cells relates to cholangitis in primary biliary cirrhosis
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DOI：
10.1002/hep.20705
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发表时间：
2005-06-01
期刊：
影响因子：
13.5
通讯作者：
Nakanuma, Y
中科院分区：
文献类型：
--
作者：
Harada, K;Isse, K;Nakanuma, Y
已知过氧化物酶体增殖物激活受体-γ（PPAR-gamma）抑制促炎细胞因子的产生。在Th 1优势疾病中，PPAR γ配体可通过下调促炎细胞因子的表达来改善临床严重程度。原发性胆汁性肝硬化（PBC）的特征是慢性破坏性胆管炎与Th 1占主导地位的细胞因子环境。不寻常的免疫反应感染剂被怀疑是其发病机制的基础。我们研究了PPAR-gamma在PBC相关的胆道炎症中的意义。为此，我们进行了免疫组织化学，定量聚合酶链反应，核因子-κ B（NF-κ B）DNA结合试验，以澄清在肝内分布的过氧化物酶体增殖物激活受体γ和炎症细胞因子和过氧化物酶体增殖物激活受体γ配体在5个培养的胆管细胞系，包括一个来自PBC肝。在PBC患者的肝脏标本中，PPAR γ蛋白在肝内胆管上皮中普遍表达，而在受损胆管中，PPAR γ蛋白和mRNA的表达减少。白细胞介素-4（IL-4; Th 2型）上调培养细胞中的PPAR γ表达，但IFN-γ（Th 1型）下调。过氧化物酶体增殖物激活受体γ配体负性调节脂多糖诱导的核因子-κ B活化。此外，这种抑制作用的PPAR γ配体减弱预处理与IFN-γ。总之，过氧化物酶体增殖物激活物受体γ可能是重要的，以维持体内平衡的肝内胆管上皮细胞，其减少在胆管PBC肝脏可能与Th 1占主导地位的环境和慢性胆管炎在PBC的发展。使用PPAR γ配体进行免疫抑制可能对减轻PBC的胆道炎症具有治疗益处。
Peroxisome proliferator-activated receptor-gamma (PPAR gamma) is known to inhibit the production of proinflammatory cytokines. In Th1-predominant diseases, PPAR gamma ligands can ameliorate clinical severity by downregulating the expression of proinflammatory cytokines. Primary biliary cirrhosis (PBC) is characterized by chronic destructive cholangitis with a Th1-predominant cytokine milieu. Unusual immune responses to infectious agents are suspected to underlie its etiopathogenesis. We examined the significance of PPAR gamma in biliary inflammation in connection to PBC. To this end, we performed immunohistochemistry, quantitative polymerase chain reaction, and nuclear factor-kappaB (NF-kappa B) DNA-binding assays to clarify the intrahepatic distribution of PPAR gamma and the regulation of PPAR gamma by inflammatory cytokines and PPAR gamma ligand in five cultured biliary cell lines including one derived from PBC liver. In liver specimens from patients with PBC PPAR gamma protein was ubiquitously expressed in intrahepatic biliary epithelium, whereas the expression of PPAR gamma protein and mRNA was reduced in damaged bile ducts. PPAR gamma expression in cultured cells was upregulated by interleukin-4 (IL-4; Th2-type), but downregulated by IFN-gamma (Th1-type). PPAR gamma ligand negatively modulated lipopolysaccharide-induced NF-kappa B activation. Moreover, this inhibitory effect of PPAR gamma ligand was attenuated by pretreatment with IFN-gamma. In conclusion, PPAR gamma may be important to maintain homeostasis in the intrahepatic biliary epithelium, and its reduction in the bile ducts of PBC liver may be associated with the Th1-predominant milieu and with the development of chronic cholangitis in PBC. Immunosuppression using PPAR gamma ligands may be of therapeutic benefit to attenuate biliary inflammation in PBC.