IL-17通过NF-κB/IRF-1/SOCS1通路与IFN-γ相拮抗对SLE早发AS发挥保护作用

SLE患者具有包括AS在内的心血管系统疾病发病风险高、病变程度重的特点。疾病进程中表达增加的IL-17虽有望成为SLE等自身免疫性疾病干预和治疗的新靶点，但其对早发AS病变的影响尚不清楚。有报道显示，IL-17可以抑制普通AS的进程并具有一定的心血管保护作用，但机理不清。我们前期研究结果提示，在巨噬细胞内，IL-17可以通过显著拮抗IFN-γ的相关效应而发挥AS保护作用，这一作用可能与其增加SOCS1的表达有关。本课题拟以巨噬细胞为切入点，深入探讨IL-17通过NF-κB/IRF-1/SOCS1通路拮抗IFN-γ作用的细胞分子机理；并通过ApoE-/-lpr-/-双敲小鼠的应用，进一步探究IL-17与IFN-γ间的相互作用在SLE早发AS病变进程中的作用，为深入理解Th17/IL-17系统抗AS进程的可能途径及其分子机制提供新的思路，也为SLE早发AS的临床防治及合理用药提供实验依据。

The key pathogenic roles of Th17 cells and their main effector-interleukin-17 (IL-17) in development of autoimmune diseases have been confirmed. Blockage of IL-17 has been expected to be one of the most important treatments for patients with systemic lupus erythematosus (SLE). The patients with SLE have higher risk and more serious lesions of cardiovascular diseases, including atherosclerosis(AS), but the influence of increased expression of IL-17 in patients with SLE on the development of AS is still obscure. It has been reported that IL-17 could play protective roles on cardiovascular diseases by inhibiting progression of AS, but the underlying mechanisms need to be further addressed. Our preliminary data indicates that IL-17 shows an anti-atherosclerotic action by obviously reversing atherogenic effects of interferon-γ(IFN-γ)in macrophages possibly by increasing expression of suppressor of cytokine signaling1(SOCS1). In this study, we will detect the antagonistic effects and its underlying molecular mechanisms of IL-17 on IFN-γ in macrophages through NF-κB/IRF-1/SOCS1 pathways. We will also observe the influences of interaction between IFN-γ and IL-17 on the development of AS in SLE using ApoE-/-lpr-/- mice. In addtion, we will intensively investigate the possible approach and its underlying mechanisms about antagonistic effects of Th17/IL-17 system on the development of AS. Our study may offer new thought on clinical treatment and resonable administration for the patients with SLE.