SOCS2 como regulador de processos inflamatórios e pró-oxidativos em modelo de injúria hepática causada por sobredose de paracetamol.

Abstract

Acetaminophen has been widely used to treat pain and fever. Usually it is safe when administrated in therapeutic doses, however the overdose and the increased susceptibility can lead to severe liver injury. This stimulate an intense inflammatory response, which can change intracellular events and even enhance the injury by activation of oxidative stress. The Supressor of Cytokine Signaling (SOCS) 2 protein is able to modulate cytokine and growth factors signaling, being important in the regulation of many cellular process, including hepatic. Our study evaluates the role of SOCS2 in APAP liver injury. The challenge with an APAP toxic dose (500mg/Kg) in mice leads to a higher necrosis in SOCS2-/- mice when compared to WT mice, 2 and 12 hours after the administration. There is a greater neutrophil recruitment to necrosis area in knockout mice, and a higher expression of chemokine CXCL-1 and increased production of proinflammatory cytokines in the liver such as TNF-α and IL-6, and lower expression of the anti-inflammatory and pro-regenerative cytokines IL-10 and TGF-β, respectively. These results justify the higher necrosis found in SOCS2-/- mice after 12 hours of APAP challenge. In the time of 2 hours, we evaluated the role of oxidative stress in the generation of necrosis. In vitro results showed increased production of ROS and expression of p-ERK and p-p65 by SOCS2-/- hepatocytes. In addition, hepatocytes deficient in SOCS2 were also more sensitive to cell death in the presence of IL-6 and hydrogen peroxide. The addition of catalase in vitro and the in vivo administration resulted in reduction of cell death and necrosis, respectively, in both groups, and in animals deficient for SOCS2 necrosis reduction is more pronounced. Therefore, our study demonstrated that SOCS2 protein has a protective role, controlling pro-oxidative and inflammatory mechanisms that occur in the hepatic injury generated by APAP.