Th1 cytokine-induced downregulation of PPARgamma in human biliary cells relates to cholangitis in primary biliary cirrhosis.
Peroxisome proliferator-activated receptor-gamma (PPARgamma) is known to inhibit the production of proinflammatory cytokines. In Th1-predominant diseases, PPARgamma 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 PPARgamma in biliary inflammation in connection to PBC. To this end, we performed immunohistochemistry, quantitative polymerase chain reaction, and nuclear factor-kappaB (NF-kappaB) DNA-binding assays to clarify the intrahepatic distribution of PPARgamma and the regulation of PPARgamma by inflammatory cytokines and PPARgamma ligand in five cultured biliary cell lines including one derived from PBC liver. In liver specimens from patients with PBC, PPARgamma protein was ubiquitously expressed in intrahepatic biliary epithelium, whereas the expression of PPARgamma protein and mRNA was reduced in damaged bile ducts. PPARgamma expression in cultured cells was upregulated by interleukin-4 (IL-4; Th2-type), but downregulated by IFN-gamma (Th1-type). PPARgamma ligand negatively modulated lipopolysaccharide-induced NF-kappaB activation. Moreover, this inhibitory effect of PPARgamma ligand was attenuated by pretreatment with IFN-gamma. In conclusion, PPARgamma 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 PPARgamma ligands may be of therapeutic benefit to attenuate biliary inflammation in PBC.
Harada
Kenichi
K
Department of Human Pathology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
Isse
Kumiko
K
Kamihira
Takashi
T
Shimoda
Shinji
S
Nakanuma
Yasuni
Y
D001652:Bile Ducts / Q000378:metabolism; D001659:Biliary Tract / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D002761:Cholangitis / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism*; D004277:DNA, Single-Stranded / Q000378:metabolism; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008105:Liver Cirrhosis, Biliary / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D018417:Th1 Cells / Q000378:metabolism*; D014018:Tissue Distribution; D051193:Toll-Like Receptors; D015854:Up-Regulation
D016207:Cytokines; D004277:DNA, Single-Stranded; D008024:Ligands; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D047495:PPAR gamma; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D015847:Interleukin-4; D007371:Interferon-gamma