Ets-1调控I型IL-4R信号通路在药疹发生中的作用与机制研究

药疹是艾滋病治疗一线抗病毒药物中常见的药物超敏反应类型，且重症药疹死亡率高，其机制尚未明确，是临床用药中的重大难题。我们前期临床样本和大鼠模型研究发现，奈韦拉平（NVP）是临床抗病毒治疗药物中的首要致敏药物；NVP药疹显著上调CCL17，募集CCR4+Th2细胞，进而活化ERK和STAT6信号通路，上调表达IL-4和IL-13；但Ets-1表达水平显著下降。我们推测，NVP通过Ets-1调控Th2细胞I型IL-4R信号通路引发药疹发生。本项目拟在细胞和大鼠模型中，通过阻断IL-4Rα受体，敲除Ets-1基因，ChIP，Co-IP等实验，明确I型IL-4R受体信号通路在药疹发生中的作用，阐明Ets-1调控I型IL-4R信号通路分子机制和KC细胞坏死性凋亡与药疹关系。本项目将揭示I型IL4-R信号通路在药疹发生中的作用及Ets-1调控机制，为创制靶向IL-4及其受体的抗超敏反应药物奠定基础。

Cutaneous adverse drug reactions such as drug eruptions are common types of drug hypersensitivity in first-line antiretroviral treatment (ART) drugs for AIDS patients. The high fatality rate of severe drug eruption is a major concern in clinical medication, and the involved mechanism is not fully understood. We previously showed that Nevirapine (NVP) is the leading causative agent among clinical ART drugs for drug eruptions. Our data in rat models and clinical samples indicated that the serum CCL17 level was significantly up-regulated in NVP-induced drug eruptions, which recruited CCR4+ Th2 cells, and then activated the ERK and STAT6 signaling pathways, thus promoting the productions of IL-4 and IL-13. However, Ets-1 expression level in Th2 cells decreased significantly. We speculate that Ets-1 may play a crucial role in controlling the development of drug eruption by regulating the type I IL-4R receptor pathway in Th2 cell subset. This project aims to clarify the role of type I IL-4R receptor pathway in the development of drug eruption by using antibodies to block the IL-4Rα receptor, Ets-1 gene knockout and other technologies in employed NVP-induced Brown Norway rat drug eruption model and Th2 cell model. In addition, we employ the ChIP, Co-IP and other experiments to identify the interaction between Ets-1 and STAT6, how it activates GATA3 to promote IL-4-associated Th2 cytokine profile and the promoter sequences involved, as well as the IL-4-induced keratinocyte necroptosis, thus to elucidate the molecular mechanism of Ets-1 in regulating the type I IL-4R pathway in Th2 cells. This project will provide innovative evidence of the function and regulatory mechanism of type I IL4-R receptors in the occurrence of drug eruption, and provide a new strategy for creating anti-drug hypersensitivity drugs that targeting IL-4 and its receptor.