4.7 Article

Hepatocyte Specific gp130 Signalling Underlies APAP Induced Liver Injury

Journal

Publisher

MDPI
DOI: 10.3390/ijms23137089

Keywords

IL-11; IL-6; GP130; IL6ST; liver injury; hepatotoxicity; acetaminophen; paracetamol; liver damage

Funding

  1. National Medical Research Council (NMRC), Singapore STaR awards [NMRC/STaR/0029/2017, MOH-CIRG18nov-0002]
  2. MRC-LMS (UK)
  3. Goh Foundation
  4. Tanoto Foundation
  5. Khoo Foundation
  6. [NMRC/OFYIRG/0053/2017]

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This study investigated the role of IL11 and gp130 in APAP-induced liver injury using mouse models with conditional knockout of Il11 or gp130 in hepatocytes. The results showed that IL11/gp130 signaling contributes to liver damage and inhibits regeneration in APAP toxicity.
N-acetyl-p-aminophenol (APAP)-induced liver damage is associated with upregulation of Interleukin-11 (IL11), which is thought to stimulate IL6ST (gp130)-mediated STAT3 activity in hepatocytes, as a compensatory response. However, recent studies have found IL11/IL11RA/gp130 signaling to be hepatotoxic. To investigate further the role of IL11 and gp130 in APAP liver injury, we generated two new mouse strains with conditional knockout (CKO) of either Il11 (CKOIl11) or gp130 (CKOgp130) in adult hepatocytes. Following APAP, as compared to controls, CKOgp130 mice had lesser liver damage with lower serum Alanine Transaminase (ALT) and Aspartate Aminotransferase (AST), greatly reduced serum IL11 levels (90% lower), and lesser centrilobular necrosis. Livers from APAP-injured CKOgp130 mice had lesser ERK, JNK, NOX4 activation and increased markers of regeneration (PCNA, Cyclin D1, Ki67). Experiments were repeated in CKOIl11 mice that, as compared to wild-type mice, had lower APAP-induced ALT/AST, reduced centrilobular necrosis and undetectable IL11 in serum. As seen with CKOgp130 mice, APAP-treated CKOIl11 mice had lesser ERK/JNK/NOX4 activation and greater features of regeneration. Both CKOgp130 and CKOIl11 mice had normal APAP metabolism. After APAP, CKOgp130 and CKOIl11 mice had reduced Il6, Ccl2, Ccl5, Il1 beta, and Tnf alpha expression. These studies exclude IL11 upregulation as compensatory and establish autocrine, self-amplifying, gp130-dependent IL11 secretion from damaged hepatocytes as toxic and anti-regenerative.

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