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Anti‐fibrotic activity and enhanced interleukin‐6 production by hepatic stellate cells in response to imatinib mesylate
Author(s) -
Kim Youngchul,
Fiel Maria I.,
Albanis Efsevia,
Chou Hsin I.,
Zhang Weijia,
Khitrov Gregory,
Friedman Scott L.
Publication year - 2012
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/j.1478-3231.2012.02806.x
Subject(s) - imatinib mesylate , hepatic stellate cell , imatinib , cancer research , stromal cell , platelet derived growth factor receptor , tyrosine kinase , tyrosine kinase inhibitor , cytokine , biology , pharmacology , chemistry , medicine , receptor , endocrinology , signal transduction , growth factor , immunology , microbiology and biotechnology , myeloid leukemia , cancer
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. Design 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. Methods and 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.