The Role of Interferon-Induced Proteins with Tetratricopeptide Repeats 1 and 2 in Sepsis-Induced Acute Liver Injury.

Background: Sepsis refers to a life-threatening organ dysfunction which can be resulted from the infection-induced dysregulated host response. A large number of inflammatory cytokines are released to act on the liver, making the liver one of the common target organs for the development of multiple organ dysfunction syndrome (MODS) in patients with sepsis. Sepsis-induced acute liver injury (SALI) can aggravate systemic disease. As a result, it is of great clinical significance to comprehend the molecular biological mechanism of SALI and to identify the markers for evaluating SALI. Interferon-induced proteins with tetratricopeptide repeats 1 and 2 (IFIT1, IFIT2) have been recognized as the anti-inflammatory factors that are widely expressed in various organs. The present study was aimed at clarifying the roles of IFIT1 and IFIT2 in the development of SALI. Methods: A two-sample Mendelian randomization (MR) analysis was employed. Summary statistics datas were obtained from GWAS for inflammatory factors [tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6)], IFIT2, and sepsis as well as liver injury. Independent SNPs were selected as instrumental variables (IVs). Inverse variance weighted (IVW) in the MR analysis was adopted as the primary method for estimating the causal associations of inflammatory factors and IFIT2 with two diseases, and the associations of inflammatory factors with IFIT2. Additionally, weighted median method, MR-Egger and sensitivity analyses were applied in assessing the robustness of the results and ensure the result reliability. Subsequently, 119 healthy volunteers, 116 patients with sepsis and 116 SALI patients were recruited. The ELISA method was employed to quantify the expression levels of TNF-α, IL-1β, and IL-6. Additionally, qRT-PCR was conducted to measure the expression of IFIT1 and IFIT2. Furthermore, the correlations of IFIT1 and IFIT2 with inflammatory factors, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were explored. Results: As shown by the MR analysis, the genetically predisposed sepsis was significantly associated with the risk of IL-1β, with an odds ratio (OR) of 1.069 (95% confidence interval (CI), 1.015-1.127, p = 0.0119), and negatively associated with the risk of IL-6, with an OR of 0.880 (95% CI: 0.792-0.979, p= 0.0184). Meanwhile, there were positive causal effects of IL-6 (OR = 1.269, 95% CI: 1.032-1.561, p= 0.0238), IL-1β (OR = 1.106, 95% CI: 1.010-1.211, p = 0.0299) and IFIT2 (OR = 1.191, 95% CI: 1.045-1.359, p = 0.0090) on liver injury. Additionally, there was a positive causal effect of IFIT2 (OR = 1.164, 95% CI: 1.035-1.309, p= 0.0110) on IL-1β. Upon sensitivity analyses, there was weak evidence of such effects, indicating that the findings of this study were robust and reliable. Our results revealed the elevated levels of TNF-α, IL-1β, and IL-6 in the blood samples of sepsis and SALI patients (p < 0.0001). Conversely, IFIT1 and IFIT2 demonstrated the significantly decreased levels in peripheral blood mononuclear cells (PBMCs) of SALI patients (p < 0.0001). Furthermore, the expression levels of IFIT1 and IFIT2 were both negatively correlated with ALT activity (r = -0.3426, p = 0.0002; r = -0.3069, p = 0.0008) and AST activity (r = -0.2483, p = 0.0072; r = -0.3261, p = 0.0004), respectively. Moreover, the expression of IFIT1 and IFIT2 was both negatively related to the levels of TNF-α (r = -0.5027, p < 0.0001; r = -0.4218, p < 0.0001), IL-1β (r = -0.3349, p = 0.0002; r = -0.4070, p < 0.0001) and IL-6 (r = -0.2734, p = 0.0030; r = -0.3536, p < 0.0001), respectively. Conclusion: IFIT1 and IFIT2 can serve as the diagnostic markers for sepsis-related liver injury, and IFIT1 and IFIT2 may participate in the pathological process of sepsis-related liver injury by regulating inflammation and liver function.