Tian Z, Shen X, Feng H, Gao B
Department of Pharmacology and Toxicology, Medical College of Virginia Commonwealth University, Richmond 23298, USA.
J Immunol. 2000 Oct 1;165(7):3959-65. doi: 10.4049/jimmunol.165.7.3959.
IFN-alphabeta is the only established treatment for viral hepatitis; however, more than 60% of patients are poorly responsive. Because viral hepatitis is associated with inflammation, we hypothesized that inflammation may attenuate the efficacy of IFN therapy. To test this hypothesis, the effect of IL-1beta, one of the major proinflammatory cytokines, on IFN signaling pathway in the liver was examined. Administration of IL-1beta in vivo attenuated IFN-alphabeta-induced STAT1 tyrosine phosphorylation in the liver but not in the spleen. The inhibitory action of IL-1beta in vivo was not affected by depleting hepatic Kupffer cells, suggesting that IL-1beta may directly target IFN-alphabeta signaling in hepatocytes. Indeed, pretreatment of human hepatocellular carcinoma HepG2 cells with IL-1beta suppressed IFN-alphabeta-induced antiviral activity and antiviral protein MxA mRNA expression. Furthermore, IL-1beta attenuated IFN-alphabeta-induced STAT1 binding and tyrosine phosphorylation without affecting the level of STAT1 protein. This inhibitory effect can be reversed by pretreatment with either proteasome inhibitors or transfection of dominant negative NF-kappaB inducing kinase mutants. Taken together, these findings suggest that IL-1beta attenuates IFN-alphabeta-induced STAT1 activation by a proteasome-dependent mechanism. In view of high levels of IL-1beta in the serum or within the liver of patients with chronic liver diseases, attenuation of IFN-alphabeta signaling in the liver by IL-1beta could be one of the mechanisms underlying the resistance to IFN therapy in chronic hepatitis C, and IL-1beta could be a potential therapeutic target for improving the efficacy of IFN therapy.
干扰素αβ是目前唯一已确立的病毒性肝炎治疗方法；然而，超过60%的患者反应不佳。由于病毒性肝炎与炎症相关，我们推测炎症可能会削弱干扰素治疗的疗效。为了验证这一假设，我们研究了主要促炎细胞因子之一白细胞介素-1β对肝脏中干扰素信号通路的影响。体内给予白细胞介素-1β可减弱肝脏中干扰素αβ诱导的信号转导和转录激活因子1（STAT1）酪氨酸磷酸化，但对脾脏无此作用。体内白细胞介素-1β的抑制作用不受肝脏库普弗细胞耗竭的影响，这表明白细胞介素-1β可能直接作用于肝细胞中的干扰素αβ信号。事实上，用白细胞介素-1β预处理人肝癌HepG2细胞可抑制干扰素αβ诱导的抗病毒活性和抗病毒蛋白MxA mRNA表达。此外，白细胞介素-1β可减弱干扰素αβ诱导的STAT1结合和酪氨酸磷酸化，而不影响STAT1蛋白水平。用蛋白酶体抑制剂预处理或转染显性负性核因子κB诱导激酶突变体可逆转这种抑制作用。综上所述，这些发现表明白细胞介素-1β通过蛋白酶体依赖性机制减弱干扰素αβ诱导的STAT1激活。鉴于慢性肝病患者血清或肝脏中白细胞介素-1β水平较高，白细胞介素-1β对肝脏中干扰素αβ信号的减弱可能是慢性丙型肝炎对干扰素治疗耐药的机制之一，白细胞介素-1β可能是提高干扰素治疗疗效的潜在治疗靶点。
