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Roles of NF‐kB and STAT3 in CXC chemokine‐mediated hepatocyte proliferation and cell death
Author(s) -
Clarke Callisia N,
Sakai Nozomo,
Tevar Amit D,
Edwards Michael J,
Lentsch Alex B
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.236.3
Subject(s) - chemokine , hepatocyte , chemistry , stat3 , hepatocyte growth factor , cell growth , cxc chemokine receptors , cancer research , pharmacology , in vitro , apoptosis , biology , inflammation , immunology , chemokine receptor , biochemistry , receptor
BACKGROUND CXC chemokines have divergent effects on hepatocytes. After hepatic I/R CXC chemokines are expressed at high levels and promote liver injury. After partial hepatectomy, they are expressed at low levels and promote proliferation. Previous studies show that chemokines are proliferative at all doses, hepatoprotective at low concentrations, while cytotoxic at high concentrations. Here we explore the roles of NF‐kB and STAT3 in regulating the effects of CXC chemokines in hepatocytes. METHODS Hepatocytes isolated from Balb/c mice were stimulated with media alone, or with MIP‐2 at low (10 ng/ml) or high (10,000 ng/ml) concentrations in the presence or absence of inhibitors of NF‐kB (BAY 11‐7085) or STAT3 (AG490) for 24 hrs. Cell death was determined by release of LDH and cell proliferation by DNA incorporation of BrdU. RESULTS Stimulation of hepatocytes with low dose MIP‐2 resulted in decreased cellular injury and increased proliferation. Blockade of NF‐kB resulted in massive hepatocyte cell death. Blockade of STAT3 resulted in abrogation of the protective effects of low‐dose MIP‐2. Blockade of STAT3 resulted in a decrease in hepatocyte proliferation with or without MIP‐2. CONCLUSIONS NF‐kB activation is required for hepatocyte viability in vivo. The hepatoprotective effect of low concentrations of CXC chemokines is STAT3 dependent. STAT3 is required for hepatocyte proliferation in vitro.