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

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.