Th1 cytokine-induced downregulation of PPARγ in human biliary cells relates to cholangitis in primary biliary cirrhosis

Kenichi Harada, Kumiko Isse, Takashi Kamihira, Shinji Shimoda, Yasuni Nakanuma

研究成果: ジャーナルへの寄稿記事

49 引用 (Scopus)

抄録

Peroxisome proliferator-activated receptor-γ (PPARγ) is known to inhibit the production of proinflammatory cytokines. In Th1-predominant diseases, PPARγ 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 PPARγ in biliary inflammation in connection to PBC. To this end, we performed immunohistochemistry, quantitative polymerase chain reaction, and nuclear factor-kappaB (NF-κB) DNA-binding assays to clarify the intrahepatic distribution of PPARγ and the regulation of PPARγ by inflammatory cytokines and PPARγ ligand in five cultured biliary cell lines including one derived from PBC liver. In liver specimens from patients with PBC, PPARγ protein was ubiquitously expressed in intrahepatic biliary epithelium, whereas the expression of PPARγ protein and mRNA was reduced in damaged bile ducts. PPARγ expression in cultured cells was upregulated by interleukin-4 (IL-4; Th2-type), but downregulated by IFN-γ (Th1-type). PPARγ ligand negatively modulated lipopolysaccharide-induced NF-κB activation. Moreover, this inhibitory effect of PPARγ ligand was attenuated by pretreatment with IFN-γ. In conclusion, PPARγ 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 PPARγ ligands may be of therapeutic benefit to attenuate biliary inflammation in PBC.

元の言語英語
ページ(範囲)1329-1338
ページ数10
ジャーナルHepatology
41
発行部数6
DOI
出版物ステータス出版済み - 6 1 2005

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Peroxisome Proliferator-Activated Receptors
Cholangitis
Biliary Liver Cirrhosis
Down-Regulation
Cytokines
Ligands
Bile Ducts
Interleukin-4
Cultured Cells
Liver
Epithelium
Inflammation
Immunosuppression
Lipopolysaccharides
Proteins
Homeostasis

All Science Journal Classification (ASJC) codes

  • Hepatology

これを引用

Th1 cytokine-induced downregulation of PPARγ in human biliary cells relates to cholangitis in primary biliary cirrhosis. / Harada, Kenichi; Isse, Kumiko; Kamihira, Takashi; Shimoda, Shinji; Nakanuma, Yasuni.

:: Hepatology, 巻 41, 番号 6, 01.06.2005, p. 1329-1338.

研究成果: ジャーナルへの寄稿記事

Harada, Kenichi ; Isse, Kumiko ; Kamihira, Takashi ; Shimoda, Shinji ; Nakanuma, Yasuni. / Th1 cytokine-induced downregulation of PPARγ in human biliary cells relates to cholangitis in primary biliary cirrhosis. :: Hepatology. 2005 ; 巻 41, 番号 6. pp. 1329-1338.
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abstract = "Peroxisome proliferator-activated receptor-γ (PPARγ) is known to inhibit the production of proinflammatory cytokines. In Th1-predominant diseases, PPARγ 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 PPARγ in biliary inflammation in connection to PBC. To this end, we performed immunohistochemistry, quantitative polymerase chain reaction, and nuclear factor-kappaB (NF-κB) DNA-binding assays to clarify the intrahepatic distribution of PPARγ and the regulation of PPARγ by inflammatory cytokines and PPARγ ligand in five cultured biliary cell lines including one derived from PBC liver. In liver specimens from patients with PBC, PPARγ protein was ubiquitously expressed in intrahepatic biliary epithelium, whereas the expression of PPARγ protein and mRNA was reduced in damaged bile ducts. PPARγ expression in cultured cells was upregulated by interleukin-4 (IL-4; Th2-type), but downregulated by IFN-γ (Th1-type). PPARγ ligand negatively modulated lipopolysaccharide-induced NF-κB activation. Moreover, this inhibitory effect of PPARγ ligand was attenuated by pretreatment with IFN-γ. In conclusion, PPARγ 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 PPARγ ligands may be of therapeutic benefit to attenuate biliary inflammation in PBC.",
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T1 - Th1 cytokine-induced downregulation of PPARγ in human biliary cells relates to cholangitis in primary biliary cirrhosis

AU - Harada, Kenichi

AU - Isse, Kumiko

AU - Kamihira, Takashi

AU - Shimoda, Shinji

AU - Nakanuma, Yasuni

PY - 2005/6/1

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N2 - Peroxisome proliferator-activated receptor-γ (PPARγ) is known to inhibit the production of proinflammatory cytokines. In Th1-predominant diseases, PPARγ 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 PPARγ in biliary inflammation in connection to PBC. To this end, we performed immunohistochemistry, quantitative polymerase chain reaction, and nuclear factor-kappaB (NF-κB) DNA-binding assays to clarify the intrahepatic distribution of PPARγ and the regulation of PPARγ by inflammatory cytokines and PPARγ ligand in five cultured biliary cell lines including one derived from PBC liver. In liver specimens from patients with PBC, PPARγ protein was ubiquitously expressed in intrahepatic biliary epithelium, whereas the expression of PPARγ protein and mRNA was reduced in damaged bile ducts. PPARγ expression in cultured cells was upregulated by interleukin-4 (IL-4; Th2-type), but downregulated by IFN-γ (Th1-type). PPARγ ligand negatively modulated lipopolysaccharide-induced NF-κB activation. Moreover, this inhibitory effect of PPARγ ligand was attenuated by pretreatment with IFN-γ. In conclusion, PPARγ 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 PPARγ ligands may be of therapeutic benefit to attenuate biliary inflammation in PBC.

AB - Peroxisome proliferator-activated receptor-γ (PPARγ) is known to inhibit the production of proinflammatory cytokines. In Th1-predominant diseases, PPARγ 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 PPARγ in biliary inflammation in connection to PBC. To this end, we performed immunohistochemistry, quantitative polymerase chain reaction, and nuclear factor-kappaB (NF-κB) DNA-binding assays to clarify the intrahepatic distribution of PPARγ and the regulation of PPARγ by inflammatory cytokines and PPARγ ligand in five cultured biliary cell lines including one derived from PBC liver. In liver specimens from patients with PBC, PPARγ protein was ubiquitously expressed in intrahepatic biliary epithelium, whereas the expression of PPARγ protein and mRNA was reduced in damaged bile ducts. PPARγ expression in cultured cells was upregulated by interleukin-4 (IL-4; Th2-type), but downregulated by IFN-γ (Th1-type). PPARγ ligand negatively modulated lipopolysaccharide-induced NF-κB activation. Moreover, this inhibitory effect of PPARγ ligand was attenuated by pretreatment with IFN-γ. In conclusion, PPARγ 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 PPARγ ligands may be of therapeutic benefit to attenuate biliary inflammation in PBC.

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