Omega‑3 polyunsaturated fatty acids inhibit IL‑11/STAT3 signaling in hepatocytes during acetaminophen hepatotoxicity

Abstract

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) exert a negative effect on IL-6 production in several liver disorders, including cirrhosis, acute liver failure and fatty liver disease. However, its effect on the production of IL-11, another important IL-6 family cytokine, remains unclear. IL-11 was found to be significantly elevated in acetaminophen (APAP)-induced liver damage. The aim of the present study was to investigate whether and how n-3 PUFAs modulate IL-11 production during APAP-induced liver injury. For that purpose, wild-type (WT) and fat-1 transgenic mice were intraperitoneally injected with APAP to induce liver injury. Serum was collected for ELISA and alanine aminotransferase assay. The hepatocytes of APAP-injected mice were isolated for reverse transcription-quantitative PCR and western blot analyses. For the in vitro study, primary hepatocytes isolated from WT or fat-1 mice were stimulated with APAP. The results revealed that both endogenous and exogenous n-3 PUFAs significantly aggravated APAP-induced liver damage via the downregulation of STAT3 signaling. Notably, n-3 PUFAs inhibited IL-11 expression, but not IL-6 expression in hepatocytes during the APAP challenge. Furthermore, it was demonstrated that limited phosphorylation of ERK1/2 and Fos-like-1 (Fra-1) expression are responsible for the n-3 PUFA-mediated inhibitory effect on IL-11 production in APAP-treated hepatocytes. It was concluded that n-3 PUFAs inhibit IL-11 production and further STAT3 activation in hepatocytes during APAP-induced liver injury. Therefore, ERK1/2-mediated Fra-1 expression is responsible for the effect of n-3 PUFAs on IL-11 expression.

Acetaminophen-Induced Hepatotoxicity in Obesity and Nonalcoholic Fatty Liver Disease: A Critical Review

“…For instance, palmitic and stearic acids could be particularly harmful by promoting hepatic CYP2E1 induction [ 74 , 98 , 99 ], as previously mentioned. Furthermore, studies carried out in transgenic fat-1 mice, which endogenously convert n-6 PUFAs to n-3 PUFAs, showed that male animals were more susceptible to APAP-induced acute liver injury, possibly via a JNK-dependent mechanism and downregulation of signal transducer and activator of transcription 3 (STAT3) [ 109 , 110 ].…”

Chronic Kidney Disease Diets for Kidney Failure Prevention: Insights from the IL-11 Paradigm

“…This mechanism was also at work in other tissues. Mitigation of acetaminophen toxicity by ω3FA depends on the inhibition of IL-11 expression and phosphorylation of ERK1/2, thus blocking hepatic injury [145]. In human breast cancer cells, DHA inhibits gremlin-1 (GREM1), thereby preventing the activation of the ERK/N-cadherin/Slug axis and partial EMT [146].…”

The immunological mechanisms and therapeutic potential in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity

“…APAP highly induces IL-11 secretion by hepatocytes, and IL-11 deficient mice exhibit spontaneous liver repair [ 212 ], however some studies demonstrate that IL-11 expression has compensatory and cytoprotective effects [ 213 ]. Omega‑3 polyunsaturated fatty acids exacerbate AILI by modulating extracellular regulated protein kinases (ERK)1/2-mediated Fra 1 expression to inhibit the production of IL-11 and further activate downstream signal transducer and activator of transcription 3 (STAT3) in hepatocytes [ 214 ]. However, a recent study suggested that upregulated IL-11 drives APAP-induced hepatocyte death, and specific deleting IL-11RA1 in hepatocytes or IL-11 knockdown in mice protected against AILI [ 215 ].…”