Dexamethasone restores transforming growth factor-β activated kinase 1 expression and phagocytosis activity of Kupffer cells in cholestatic liver injury

Dexamethasone restores transforming growth factor-β activated kinase 1 expression and... The role of transforming growth factor-β activated kinase 1 (TAK1) in modulating the function of Kupffer cells (KCs) within cholestatic livers remains unclear. This study examined the immunopharmacological action of dexamethasone (DEX) in modulating hepatic TAK1 expression and related signaling activity in a rat model of bile duct ligation-mimicked obstructive jaundice. The in vitro effects of DEX on porcine biliary extract (PBE)-modulated gene expression and phagocytosis of KCs were examined using a rat alveolar macrophage cell line (NR8383 cells). Although DEX therapy did not restore the downregulated TAK1 expression and phosphorylation, it significantly attenuated the upregulation of high-mobility group box 1 expression and caspase-3 activation in whole liver extracts of cholestatic rats, possibly via enhancing extracellular signal-regulated kinase-mediated signaling. Dual immunofluorescence staining of cholestatic livers and western detection on primary KCs isolated from cholestatic livers identified that DEX treatment indeed increased both the expression and phosphorylation levels of TAK1 in the KCs of cholestatic livers. In vitro studies using alveolar NR8383 macrophages with KC-characteristic gene expression further demonstrated that DEX not only repressed the pro-inflammatory cytokine production including with respect to interleukin (IL)-1β and IL-6, but also enhanced gene expression of TAK1 and a phagocytic marker, natural-resistance-associated macrophage protein 1, under PBE-mimicked cholestatic conditions. However, WST-1 assay showed that DEX did not protect NR8383 macrophages against the PBE-induced cytotoxicity. Immunofluorescence visualization of cellular F-actin by phalloidin suggested that DEX sustained the PBE-induced phagocytosis morphology of NR8383 macrophages. In conclusion, DEX treatment may pharmacologically restore the expression and activity of TAK1 in KCs, and sustain the phagocytic phenotype of KCs in cholestatic livers. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png International Immunopharmacology Elsevier

Dexamethasone restores transforming growth factor-β activated kinase 1 expression and phagocytosis activity of Kupffer cells in cholestatic liver injury

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Publisher
Elsevier
Copyright
Copyright © 2018 Elsevier Ltd
ISSN
1567-5769
eISSN
1878-1705
D.O.I.
10.1016/j.intimp.2018.01.047
Publisher site
See Article on Publisher Site

Abstract

The role of transforming growth factor-β activated kinase 1 (TAK1) in modulating the function of Kupffer cells (KCs) within cholestatic livers remains unclear. This study examined the immunopharmacological action of dexamethasone (DEX) in modulating hepatic TAK1 expression and related signaling activity in a rat model of bile duct ligation-mimicked obstructive jaundice. The in vitro effects of DEX on porcine biliary extract (PBE)-modulated gene expression and phagocytosis of KCs were examined using a rat alveolar macrophage cell line (NR8383 cells). Although DEX therapy did not restore the downregulated TAK1 expression and phosphorylation, it significantly attenuated the upregulation of high-mobility group box 1 expression and caspase-3 activation in whole liver extracts of cholestatic rats, possibly via enhancing extracellular signal-regulated kinase-mediated signaling. Dual immunofluorescence staining of cholestatic livers and western detection on primary KCs isolated from cholestatic livers identified that DEX treatment indeed increased both the expression and phosphorylation levels of TAK1 in the KCs of cholestatic livers. In vitro studies using alveolar NR8383 macrophages with KC-characteristic gene expression further demonstrated that DEX not only repressed the pro-inflammatory cytokine production including with respect to interleukin (IL)-1β and IL-6, but also enhanced gene expression of TAK1 and a phagocytic marker, natural-resistance-associated macrophage protein 1, under PBE-mimicked cholestatic conditions. However, WST-1 assay showed that DEX did not protect NR8383 macrophages against the PBE-induced cytotoxicity. Immunofluorescence visualization of cellular F-actin by phalloidin suggested that DEX sustained the PBE-induced phagocytosis morphology of NR8383 macrophages. In conclusion, DEX treatment may pharmacologically restore the expression and activity of TAK1 in KCs, and sustain the phagocytic phenotype of KCs in cholestatic livers.

Journal

International ImmunopharmacologyElsevier

Published: Mar 1, 2018

References

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