title: Anti-fibrotic activity and enhanced interleukin-6 production by hepatic stellate cells in response to imatinib mesylate.
abstract: OBJECTIVE
  To examine imatinib mesylate's effects on stellate cell responses in vivo and in vitro. The hepatic stellate cell (HSC) is a key target of anti-fibrotic therapies. Imatinib mesylate is a small molecule receptor tyrosine kinase inhibitor indicated for treatment of chronic myelogenous leukaemia and GI stromal tumours.
  
  
  METHODS
  Because imatinib inhibits β-PDGFR signalling, which stimulates HSC proliferation, we assessed its activity in culture and in vivo, and examined downstream targets in a human stellate cell line (LX-2) using cDNA microarray.
  
  
  RESULTS
  Imatinib inhibited proliferation of LX-2 cells (0.5-10 mM) but not primary human stellate cells, with no effect on viability, associated with attenuated β-PDGFR phosphorylation. Mitochondrial activity and superoxide anion production were decreased in response to imatinib. cDNA microarray uncovered up-regulation of 29 genes in response to imatinib, including interleukin-6 (IL-6) mRNA, which was correlated with progressive IL-6 secretion. Imatinib also decreased gene expression of collagen α(1) (I), alpha smooth muscle actin, β-PDGFR, transforming growth factor β receptor type 1, matrix metalloproteinase 2 and tissue inhibitor of metalloproteinase 2. In vivo, imatinib administered to rats beginning 4 weeks after starting thioacetamide (TAA) led to reduced collagen content, with significant reductions in portal pressure and down-regulation of fibrogenic genes in whole liver. Importantly, hepatic IL-6 mRNA levels were significantly increased in TAA-treated animals receiving imatinib.
  
  
  CONCLUSIONS
  These findings reinforce the anti-fibrotic activity of imatinib and uncover an unexpected link between inhibition of HSC activation by imatinib and enhanced secretion of IL-6, a regenerative cytokine.
authors.affiliation: Division of Liver Diseases, Department of Medicine, The Mount Sinai School of Medicine, New York, NY 10029-6574, USA.
authors.forename: Youngchul
authors.initials: Y
authors.lastname: Kim
authors.forename: Maria I
authors.initials: MI
authors.lastname: Fiel
authors.forename: Efsevia
authors.initials: E
authors.lastname: Albanis
authors.forename: Hsin I
authors.initials: HI
authors.lastname: Chou
authors.forename: Weijia
authors.initials: W
authors.lastname: Zhang
authors.forename: Gregory
authors.initials: G
authors.lastname: Khitrov
authors.forename: Scott L
authors.initials: SL
authors.lastname: Friedman
mesh_terms: D000818:Animals; D001549:Benzamides; D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling / Q000379:methods; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D013853:Thioacetamide; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D001549:Benzamides; D015415:Biomarkers; C508600:IL6 protein, human; D015850:Interleukin-6; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D013853:Thioacetamide; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta