Infliximab and Dexamethasone Attenuate the Ductular Reaction in Mice

Verhulst, Stefaan; Best, Jan; Syn, Wing–Kin; Reynaert, Hendrik; Hellemans, Karine; Canbay, Ali; Dollé, Laurent; Grunsven, Leo A. van

doi:10.1038/srep36586

Cited by 6 publications

(3 citation statements)

References 53 publications

(62 reference statements)

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“…With respect to HPC activation, the TNF α antagonist Infliximab could inhibit HPC activation and fibrosis in both a mouse model of steatosis and cholestasis. 43 However, while early clinical trials with alcoholic hepatitis patients have shown promising results with the single treatment with Infliximab, 44 , 45 randomised trials using either IFX or Etanercept (soluble TNF receptor) were disappointing. 46 , 47 …”

Section: Discussionmentioning

confidence: 99%

RNA-sequencing-based comparative analysis of human hepatic progenitor cells and their niche from alcoholic steatohepatitis livers

et al. 2017

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Hepatic progenitor cells (HPCs) are small cells with a relative large oval nucleus and a scanty cytoplasm situated in the canals of Hering that express markers of (immature) hepatocytes and cholangiocytes. HPCs are present in large numbers in alcoholic steatohepatitis (ASH), one of the leading causes of chronic liver disease. To date, the mechanisms responsible for proliferation and differentiation of human HPCs are still poorly understood and the role of HPCs in ASH development is unknown. In this study, we aimed to characterise human HPCs and their interactions with other cells through comparison, on both protein and RNA level, of HPC-enriched cell populations from adult human liver tissue using different isolation methods. Fresh human liver tissue was collected from ASH explant livers and HPC-enriched cell populations were obtained via four different isolation methods: side population (SP), epithelial cell adhesion molecule (EpCAM) and trophoblast antigen 2 (TROP-2) membrane marker isolation and laser capture microdissection. Gene expression profiles of fluorescent-activated cell-sorted HPCs, whole liver extracts and laser microdissected HPC niches were determined by RNA-sequencing. Immunohistochemical evaluation of the isolated populations indicated the enrichment of HPCs in the SP, EpCAM+ and TROP-2+ cell populations. Pathway analysis of the transcription profiles of human HPCs showed an enrichment and activation of known HPC pathways like Wnt/β-catenin, TWEAK and HGF. Integration of the HPC niche profile suggests autocrine signalling by HPCs (TNFα, PDGFB and VEGFA) as well as paracrine signalling from the surrounding niche cells including MIF and IGF-1. In addition, we identified IL-17 A signalling as a potentially novel pathway in HPC biology. In conclusion, we provide the first RNA-seq-based, comparative transcriptome analysis of isolated human HPCs from ASH patients and revealed active signalling between HPCs and their surrounding niche cells in ASH livers and suggest that HPCs can actively contribute to liver inflammation.

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Section: Discussionmentioning

confidence: 99%

RNA-sequencing-based comparative analysis of human hepatic progenitor cells and their niche from alcoholic steatohepatitis livers

et al. 2017

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“…Enhanced levels of TNF have also been detected in Mdr2 −/− mice compared to wild-type mice [ 105 ]. A preclinical functional study in the DDC model indicated that anti-TNF treatment had no effect on serum levels of liver enzymes but prevented the ductular reaction as well as extracellular matrix deposition in mouse livers [ 116 ]. We wondered whether TNF would affect liver inflammation, liver damage, and fibrosis in chronic experimental sclerosing cholangitis in the Mdr2 −/− mouse model.…”

Section: Role Of Tnf In Autoimmune Liver Disease (Aild)mentioning

confidence: 99%

TNF in the liver: targeting a central player in inflammation

Tiegs

Horst

2022

Semin Immunopathol

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Tumour necrosis factor-α (TNF) is a multifunctional cytokine. First recognized as an endogenous soluble factor that induces necrosis of solid tumours, TNF became increasingly important as pro-inflammatory cytokine being involved in the immunopathogenesis of several autoimmune diseases. In the liver, TNF induces numerous biological responses such as hepatocyte apoptosis and necroptosis, liver inflammation and regeneration, and autoimmunity, but also progression to hepatocellular carcinoma. Considering these multiple functions of TNF in the liver, we propose anti-TNF therapies that specifically target TNF signalling at the level of its specific receptors.

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“…Observational studies show that estrogen therapy is an important risk factor in gallbladder disease [ 46 , 47 ]. Studies on experimental models also suggested a beneficial effect of GC treatment, such as dexamethasone, for attenuation of ductular impairment [ 48 , 49 ]. Our data from the MDR2KO mouse model, showing cholangiocyte hyperplasia and hepatic fibrosis being more pronounced in females than in males, and being partially reduced by corticosterone treatment, are in agreement with these reports.…”

Section: Discussionmentioning

confidence: 99%

Glucocorticoids Cause Gender-Dependent Reversal of Hepatic Fibrosis in the MDR2-Knockout Mouse Model

Petrescu¹,

Grant²,

Frampton³

et al. 2017

IJMS

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Hepatic cholestasis is associated with a significant suppression of the hypothalamus-pituitary-adrenal axis (HPA). In the present study, we tested the hypothesis that activation of the HPA axis by corticosterone treatment can reverse liver inflammation and fibrosis in a multidrug resistance protein 2 knockout (MDR2KO) transgenic mouse model of hepatic cholestasis. Friend Virus B NIH-Jackson (FVBN) control and MDR2KO male and female mice were treated with vehicle or corticosterone for two weeks, then serum and liver analyses of hepatic cholestasis markers were performed. Indicators of inflammation, such as increased numbers of macrophages, were determined. MDR2KO mice had lower corticotropin releasing hormone and corticosterone levels than FVBN controls in the serum. There was a large accumulation of CD68 and F4/80 macrophages in MDR2KO mice livers, which indicated greater inflammation compared to FVBNs, an effect reversed by corticosterone treatment. Intrahepatic biliary duct mass, collagen deposition and alpha smooth muscle actin (αSMA) were found to be much higher in livers of MDR2KO mice than in controls; corticosterone treatment significantly decreased these fibrosis markers. When looking at the gender-specific response to corticosterone treatment, male MDR2KO mice tended to have a more pronounced reversal of liver fibrosis than females treated with corticosterone.

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Infliximab and Dexamethasone Attenuate the Ductular Reaction in Mice

Cited by 6 publications

References 53 publications

RNA-sequencing-based comparative analysis of human hepatic progenitor cells and their niche from alcoholic steatohepatitis livers

RNA-sequencing-based comparative analysis of human hepatic progenitor cells and their niche from alcoholic steatohepatitis livers

TNF in the liver: targeting a central player in inflammation

Glucocorticoids Cause Gender-Dependent Reversal of Hepatic Fibrosis in the MDR2-Knockout Mouse Model

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