The pro-regenerative effects of hyperIL6 in drug-induced liver injury are unexpectedly due to competitive inhibition of IL11 signaling

It is generally accepted that IL6-mediated STAT3 signaling in hepatocytes, mediated via glycoprotein 130 (gp130; IL6ST), is beneficial and that the synthetic IL6:IL6ST fusion protein (HyperIL6) promotes liver regeneration. Recently, autocrine IL11 activity that also acts via IL6ST but uses ERK rathe...

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Autores principales:	Jinrui Dong, Sivakumar Viswanathan, Eleonora Adami, Sebastian Schafer, Fathima F Kuthubudeen, Anissa A Widjaja, Stuart A Cook
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	IL11 liver injury IL6 Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/ea89d86a78a24e6f81b5cc924937a290
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spelling	oai:doaj.org-article:ea89d86a78a24e6f81b5cc924937a2902021-11-26T07:06:14ZThe pro-regenerative effects of hyperIL6 in drug-induced liver injury are unexpectedly due to competitive inhibition of IL11 signaling10.7554/eLife.688432050-084Xe68843https://doaj.org/article/ea89d86a78a24e6f81b5cc924937a2902021-08-01T00:00:00Zhttps://elifesciences.org/articles/68843https://doaj.org/toc/2050-084XIt is generally accepted that IL6-mediated STAT3 signaling in hepatocytes, mediated via glycoprotein 130 (gp130; IL6ST), is beneficial and that the synthetic IL6:IL6ST fusion protein (HyperIL6) promotes liver regeneration. Recently, autocrine IL11 activity that also acts via IL6ST but uses ERK rather than STAT3 to signal, was found to be hepatotoxic. Here we examined whether the beneficial effects of HyperIL6 could reflect unappreciated competitive inhibition of IL11-dependent IL6ST signaling. In human and mouse hepatocytes, HyperIL6 reduced N-acetyl-p-aminophenol (APAP)-induced cell death independent of STAT3 activation and instead, dose-dependently, inhibited IL11-related signaling and toxicities. In mice, expression of HyperIl6 reduced ERK activation and promoted STAT3-independent hepatic regeneration (PCNA, Cyclin D1, Ki67) following administration of either IL11 or APAP. Inhibition of putative intrinsic IL6 trans-signaling had no effect on liver regeneration in mice. Following APAP, mice deleted for Il11 exhibited spontaneous liver repair but HyperIl6, despite robustly activating STAT3, had no effect on liver regeneration in this strain. These data show that synthetic IL6ST binding proteins such as HyperIL6 can have unexpected, on-target effects and suggest IL11, not IL6, as important for liver regeneration.Jinrui DongSivakumar ViswanathanEleonora AdamiSebastian SchaferFathima F KuthubudeenAnissa A WidjajaStuart A CookeLife Sciences Publications LtdarticleIL11liver injuryIL6MedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	IL11 liver injury IL6 Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	IL11 liver injury IL6 Medicine R Science Q Biology (General) QH301-705.5 Jinrui Dong Sivakumar Viswanathan Eleonora Adami Sebastian Schafer Fathima F Kuthubudeen Anissa A Widjaja Stuart A Cook The pro-regenerative effects of hyperIL6 in drug-induced liver injury are unexpectedly due to competitive inhibition of IL11 signaling
description	It is generally accepted that IL6-mediated STAT3 signaling in hepatocytes, mediated via glycoprotein 130 (gp130; IL6ST), is beneficial and that the synthetic IL6:IL6ST fusion protein (HyperIL6) promotes liver regeneration. Recently, autocrine IL11 activity that also acts via IL6ST but uses ERK rather than STAT3 to signal, was found to be hepatotoxic. Here we examined whether the beneficial effects of HyperIL6 could reflect unappreciated competitive inhibition of IL11-dependent IL6ST signaling. In human and mouse hepatocytes, HyperIL6 reduced N-acetyl-p-aminophenol (APAP)-induced cell death independent of STAT3 activation and instead, dose-dependently, inhibited IL11-related signaling and toxicities. In mice, expression of HyperIl6 reduced ERK activation and promoted STAT3-independent hepatic regeneration (PCNA, Cyclin D1, Ki67) following administration of either IL11 or APAP. Inhibition of putative intrinsic IL6 trans-signaling had no effect on liver regeneration in mice. Following APAP, mice deleted for Il11 exhibited spontaneous liver repair but HyperIl6, despite robustly activating STAT3, had no effect on liver regeneration in this strain. These data show that synthetic IL6ST binding proteins such as HyperIL6 can have unexpected, on-target effects and suggest IL11, not IL6, as important for liver regeneration.
format	article
author	Jinrui Dong Sivakumar Viswanathan Eleonora Adami Sebastian Schafer Fathima F Kuthubudeen Anissa A Widjaja Stuart A Cook
author_facet	Jinrui Dong Sivakumar Viswanathan Eleonora Adami Sebastian Schafer Fathima F Kuthubudeen Anissa A Widjaja Stuart A Cook
author_sort	Jinrui Dong
title	The pro-regenerative effects of hyperIL6 in drug-induced liver injury are unexpectedly due to competitive inhibition of IL11 signaling
title_short	The pro-regenerative effects of hyperIL6 in drug-induced liver injury are unexpectedly due to competitive inhibition of IL11 signaling
title_full	The pro-regenerative effects of hyperIL6 in drug-induced liver injury are unexpectedly due to competitive inhibition of IL11 signaling
title_fullStr	The pro-regenerative effects of hyperIL6 in drug-induced liver injury are unexpectedly due to competitive inhibition of IL11 signaling
title_full_unstemmed	The pro-regenerative effects of hyperIL6 in drug-induced liver injury are unexpectedly due to competitive inhibition of IL11 signaling
title_sort	pro-regenerative effects of hyperil6 in drug-induced liver injury are unexpectedly due to competitive inhibition of il11 signaling
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/ea89d86a78a24e6f81b5cc924937a290
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The pro-regenerative effects of hyperIL6 in drug-induced liver injury are unexpectedly due to competitive inhibition of IL11 signaling

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