IL-6 Trans-signaling Controls Liver Regeneration After Partial Hepatectomy

被引：94

作者：

Modares, Nastaran Fazel ^{[1
]}

Polz, Robin ^{[1
]}

Haghighi, Fereshteh ^{[1
]}

Lamertz, Larissa ^{[1
]}

Behnke, Kristina ^{[2
]}

Zhuang, Yuan ^{[2
]}

Kordes, Claus ^{[3
]}

Haeussinger, Dieter ^{[3
]}

Sorg, Ursula R. ^{[4
]}

Pfeffer, Klaus ^{[4
]}

Floss, Doreen M. ^{[1
]}

Moll, Jens M. ^{[1
]}

Piekorz, Roland R. ^{[1
]}

Ahmadian, M. Reza ^{[1
]}

Lang, Philipp A. ^{[2
]}

Scheller, Juergen ^{[1
]}

机构：

[1] Heinrich Heine Univ, Med Fac, Inst Biochem & Mol Biol 2, Dusseldorf, Germany

[2] Heinrich Heine Univ, Med Fac, Inst Mol Med 2, Dusseldorf, Germany

[3] Heinrich Heine Univ, Med Fac, Clin Gastroenterol Hepatol & Infect Dis, Dusseldorf, Germany

[4] Heinrich Heine Univ, Inst Med Microbiol & Hosp Hyg, Med Fac, Dusseldorf, Germany

来源：

HEPATOLOGY | 2019年 / 70卷 / 06期

关键词：

INTERLEUKIN-6; RECEPTOR; HEPATOCYTE REGENERATION; DESIGNER CYTOKINE; MOLECULAR SWITCH; IN-VIVO; GP130; CELL; HYPERPLASIA; EXPRESSION; ADAM17;

D O I：

10.1002/hep.30774

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Interleukin-6 (IL-6) is critically involved in liver regeneration after partial hepatectomy (PHX). Previous reports suggest that IL-6 trans-signaling through the soluble IL-6/IL-6R complex is involved in this process. However, the long-term contribution of IL-6 trans-signaling for liver regeneration after PHX is unknown. PHX-induced generation of the soluble IL-6R by ADAM (a disintegrin and metallo) proteases enables IL-6 trans-signaling, in which IL-6 forms an agonistic complex with the soluble IL-6 receptor (sIL-6R) to activate all cells expressing the signal-transducing receptor chain glycoprotein 130 (gp130). In contrast, without activation of ADAM proteases, IL-6 in complex with membrane-bound IL-6R and gp130 activates classic signaling. Here, we describe the generation of IL-6 trans-signaling mice, which exhibit boosted IL-6 trans-signaling and abrogated classic signaling by genetic conversion of all membrane-bound IL-6R into sIL-6R proteins phenocopying hyperactivation of ADAM-mediated shedding of IL-6R as single substrate. Importantly, although IL-6R deficient mice were strongly affected by PHX, survival and regeneration of IL-6 trans-signaling mice was indistinguishable from control mice, demonstrating that IL-6 trans-signaling fully compensates for disabled classic signaling in liver regeneration after PHX. Moreover, we monitored the long-term consequences of global IL-6 signaling inhibition versus IL-6 trans-signaling selective blockade after PHX by IL-6 monoclonal antibodies and soluble glycoprotein 130 as fragment crystallizable fusion, respectively. Both global IL-6 blockade and selective inhibition of IL-6 trans-signaling results in a strong decrease of overall survival after PHX, accompanied by decreased signal transducer and activator of transcription 3 phosphorylation and proliferation of hepatocytes. Mechanistically, IL-6 trans-signaling induces hepatocyte growth factor production by hepatic stellate cells. Conclusion: IL-6 trans-signaling, but not classic signaling, controls liver regeneration following PHX.

引用

页码：2075 / 2091

页数：17

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