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Alcoholic liver injury (ALI) is a part of alcohol-related liver diseases. These diseases include steatohepatitis, alcoholic fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Accumulating data indicates that alcohol metabolism and circulating endotoxin/lipopolysaccharide (LPS) contribute to macrophage activation, which leads to the development of ALI. Protein tyrosine phosphatase 1B (PTP1B) has been shown to be involved in many tissue inflammations as well as liver fibrosis; however, the role of PTP1B in ALI is still unclear. In this study, PTP1B expression was elevated in liver tissues and primary macrophages isolated from EtOH-fed mice. Moreover, PTP1B expression was elevated in RAW264.7 cells stimulated with alcohol and LPS. Additional studies showed that silencing of PTP1B reduced the inflammatory response and expression of inflammatory cytokines such as IL-1β, IL-6 and TNF-α, while overexpression of PTP1B induced inflammation in RAW264.7 cells. In addition, we found that NF-κB pathway was activated in RAW264.7 cells stimulated with alcohol and LPS, and PTP1B silencing or overexpression could regulate NF-κB signaling. In conclusion, this study revealed the function of PTP1B in ALI via its regulation of the NF-κB signaling pathway and may provide theoretical support for further research on ALI.

Alcohol-induced liver injury (ALI) is associated with inflammatory responses regulated by macrophages. Activation of macrophages plays a crucial role in ALI while DNA methylation-regulated gene silencing is associated with inflammation processes in macrophages. Proline-Serine-Threonine Phosphatase Interacting Protein 2 (PSTPIP2), which belongs to the Fes/CIP4 homology-Bin/Amphiphysin/Rvs domain family of proteins and plays a role in macrophages. Previous studies have shown that Pstpip2 can be methylated. Herein, its expression was found to be significantly downregulated in primary liver macrophages isolated from EtOH-fed mice and EtOH-induced RAW264.7 cells. Overexpression of PSTPIP2 using liver-specific recombinant AAV serotype 9 (rAAV9)-PSTPIP2 in EtOH-fed mice dramatically alleviated liver injury and inflammatory responses. In addition, silencing of PSTPIP2 aggravated the alcohol-induced inflammatory response in vitro. Mechanistically, PSTPIP2 might affect macrophage-induced inflammatory responses by regulating the STAT1 and NF-κB signaling pathways. The downregulation of PSTPIP2 in ALI may be associated with DNA methylation. Methylation-specific PCR and western blotting analyses showed that EtOH induced abnormal DNA methylation patterns and increased the protein expression levels of DNMT1, DNMT3a, and DNMT3b. The chromatin immunoprecipitation assay showed that DNMT3a could directly bind to the Pstpip2 promoter and act as a principal regulator of PSTPIP2 expression. Moreover, silencing of DNMT3a significantly restored the EtOH-induced low expression of PSTPIP2 and inhibited EtOH-induced inflammation. Overall, these findings provide a detailed understanding of the possible functions and mechanisms of PSTPIP2 in ALI, thus providing new substantive research to elucidate the pathogenesis of ALI and investigate potential targeted treatment strategies.