Open AccessLPS‐induced inflammation desensitizes hepatocytes to Fas‐induced apoptosis through Stat3 activation—The effect can be reversed by ruxolitinib
Author(s) -
Markotic Antonio,
Flegar Darja,
Grcevic Danka,
Sucur Alan,
Lalic Hrvoje,
Turcic Petra,
Kovacic Natasa,
Lukac Nina,
Pravdic Danijel,
Vukojevic Katarina,
Cavar Ivan,
Kelava Tomislav
Publication year - 2020
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.14930
Subject(s) - stat3 , apoptosis , stat protein , inflammation , tumor necrosis factor alpha , hepatocyte , cytokine , phosphorylation , janus kinase , in vivo , signal transduction , ruxolitinib , lipopolysaccharide , cancer research , chemistry , microbiology and biotechnology , biology , immunology , in vitro , bone marrow , biochemistry , myelofibrosis
Recent studies have established a concept of tumour necrosis factor‐α (TNF‐α)/Fas signalling crosstalk, highlighting TNF‐α as a critical cytokine in sensitizing hepatocytes to death induced by Fas activation. However, in the exact inflammatory response, besides TNF‐α, many other mediators, that might modulate apoptotic response differentially, are released. To resolve the issue, we studied the effects of lipopolysaccharide (LPS), one of the crucial inductors of inflammation in the liver, on apoptotic outcome. We show that LPS‐induced inflammation diminishes the sensitivity of hepatocytes to Fas stimulus in vivo at caspase‐8 level. Analysis of molecular mechanisms revealed an increased expression of various pro‐inflammatory cytokines in non‐parenchymal liver cells and hepatocyte‐specific increase in Bcl‐xL, associated with signal transducer and activator of transcription 3 (Stat3) phosphorylation. Pre‐treatment with ruxolitinib, a selective Janus kinase (JAK) 1/2 inhibitor, prevented the LPS‐induced Stat3 phosphorylation and restored the sensitivity of hepatocytes to Fas‐mediated apoptosis. Furthermore, ruxolitinib pre‐treatment diminished the LPS‐induced Bcl‐xL up‐regulation without an inhibitory effect on LPS‐induced expression of pro‐inflammatory cytokines. In summary, although the reports are showing that the effects of isolated pro‐inflammatory mediators, such as TNF‐α or neutrophils, are pro‐apoptotic, the overall effect of inflammatory milieu on hepatocytes in vivo is Stat3‐dependent desensitization to Fas‐mediated apoptosis.