LPS‐induced inflammation desensitizes hepatocytes to Fas‐induced apoptosis through Stat3 activation—The effect can be reversed by ruxolitinib

Abstract

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.

FasL (rs763110) gene polymorphism is not associated with susceptibility to rheumatoid arthritis in Croatian population

“…Various in vitro and in vivo studies have suggested complex crosstalk between their signaling pathways. Furthermore, it was found that TNF-α and FasL affected each other’s activity and expression ( 8 , 24 ). Therefore, we hypothesized that the rs763110 genotype might be associated with TNF-α concentration in plasma, which had not been previously investigated.…”

“…Total RNA was extracted from peripheral blood mononuclear cells using TRIzol (Invitrogen by Life Technologies [LT], Grand Island, NY, USA), converted to complementary DNA and amplified in duplicates by qPCR in an ABI Prism 7500 Sequence Detection System (Applied Biosystems by LT). Gene expression of TNF-α and glyceraldehyde 3-phosphate dehydrogenase was assessed using TaqMan Assays (Applied Biosystems by LT) and presented as RNA relative quantity, as previously described ( 8 ).…”

Janus Kinase Inhibition Ameliorates Ischemic Stroke Injury and Neuroinflammation Through Reducing NLRP3 Inflammasome Activation via JAK2/STAT3 Pathway Inhibition

“…Rux (C10891361, Shanghai Chemical Industry Park, Shanghai, China) was dissolved in 30% polyethylene glycol 300 (PEG300) and 3% dimethyl sulfoxide (DMSO) as previously described (26) and diluted with distilled water (dH2O) to the required concentrations. In the first experiment, mice were treated 30 minutes after MCAO with 4 different doses of Rux (30, 60, 90, and 120 mg/kg) by oral gavage twice daily for three days.…”

Elucidation of the Hdac2/Sp1/miR-204-5p/Bcl-2 axis as a modulator of cochlear apoptosis via in vivo/in vitro models of acute hearing loss

“…LPS induced inflammation by activating HIF1 and hypoxia pathway gene responses in the testis, 58,59 as well as apoptosis by both intrinsic and extrinsic pathways. [60][61][62] In our acute hearing loss model, LPS may induce oxidative stress, provoke inner ear cells to release inflammatory cytokines, and eventually reduce Hdac2 activity or level. 54 In the present study, we use the LPS animal model to further explore the specific mechanisms of Hdac2 in cochlear hair cell apoptosis.…”