SOCS2 Is Critical for the Balancing of Immune Response and Oxidate Stress Protecting Against Acetaminophen-Induced Acute Liver Injury

Abstract

Acetaminophen (APAP) is usually safe when administrated in therapeutic doses; however, APAP overdose can lead to severe liver injury. APAP can cause direct hepatocyte damage, and stimulates an inflammatory response leading to oxidative stress. Supressor of Cytokine Signaling (SOCS) 2 modulates cytokine and growth factor signaling, and plays a role in the regulation of hepatic cellular processes. Our study evaluated the role of SOCS2 in APAP liver injury. The administration of a toxic dose (600 mg/kg) of APAP caused significant liver necrosis in WT mice. In SOCS2−/− mice, there was significantly more necrosis, neutrophil recruitment, and expression of the neutrophil-active chemokine CXCL-1. Expression of proinflammatory cytokines, such as TNF-α and IL-6, was elevated, while expression of anti-inflammatory cytokines, IL-10 and TGF-β, was diminished. In vitro, SOCS2−/− hepatocytes expressed more p-NF-kB and produced more ROS than WT hepatocytes when exposed to APAP. SOCS2−/− hepatocytes were more sensitive to cell death in the presence of IL-6 and hydrogen peroxide. The administration of catalase in vitro and in vivo resulted in a pronounced reduction of cells/mice death and necrosis in the SOCS2−/− group. We have demonstrated that SOCS2 has a protective role in the liver by controlling pro-oxidative and inflammatory mechanisms induced by APAP.

RETRACTED ARTICLE: LncRNA HIF1A-AS1 contributes to ventricular remodeling after myocardial ischemia/reperfusion injury by adsorption of microRNA-204 to regulating SOCS2 expression

“…It has been suggested that by regulating miR-204-3p and inhibiting autophagy, downregulated expression of lncRNA AK139328 alleviated myocardial I/R injury in glycuresis mice [11]. The suppressor of cytokine signaling (SOCS) protein family was initially described as a cytokine-induced JAK/STAT signaling feedback inhibitor [12]. The evidence indicated the significance of SOCS2 in the regulation of biological processes in various diseases and cancers [13].…”

Role of SOCS2 in the Regulation of Immune Response and Development of the Experimental Autoimmune Encephalomyelitis

“…Recent studies from our group have shown an unbalanced inflammatory response in the late stages of different models. For instance, in a model of liver failure with acetaminophen overdose, SOCS2 -/mice had more necrosis, oxidation, and proinflammatory cytokines in the liver than WT mice [15]. In the cerebral malaria model, SOCS2 -/mice display increased parasitemia and reduced Treg cell infiltration in the late phase, an effect associated with increased numbers of Th1 and Th17 cells and elevated cytokine levels [11].…”

“…In these models, the participation of SOCS2 is complex and include the generation/differentiation of Th1, Th2, Th17, and T regulatory (Treg) cells [11][12][13][14]. Moreover, SOCS2 is critical to balance physiological functions of the brain, heart, and liver by controlling the production of neurotrophic factors, calcium handling, and prooxidative mechanisms [11,12,15]. The absence of SOCS2 enhanced Th2 differentiation, which contributed to the generation of type 2 allergic responses [15,16].…”

“…Moreover, SOCS2 is critical to balance physiological functions of the brain, heart, and liver by controlling the production of neurotrophic factors, calcium handling, and prooxidative mechanisms [11,12,15]. The absence of SOCS2 enhanced Th2 differentiation, which contributed to the generation of type 2 allergic responses [15,16].…”

Identification of Key Genes and Evaluation of Their Prognosis Potential in Hepatocellular Carcinoma by Integrated Bioinformatics Analysis

“…SOCS2 is involved in the inhibition of signal transduction. It has been reported that SOCS2 regulates immune response during acute liver injury, caused by acetaminophen [28]. Meanwhile, SOCS2 also plays a critical role in the development of prostate cancer [29].…”