IL-1F7b在结核分枝杆菌感染致病过程中的作用机制研究

Identification and characterization of key immune regulators in the pathogenesis of tuberculosis is essential for the development of anti-TB approaches. IL-1F7b, a member of IL-1 family, is an important anti-inflammatory cytokine as well as a fundamental inhibitor of innate immunity. It exerts both intracellular and extracellular functions. However, the potential functional role of IL-1F7b in the process of Mtb infection remains unknown. Our previous work demonstrated that two SNP sites rs6717710 C/T and rs3811047 A/G are closely associated with the occurrence of tuberculosis. We also observed that IL-1F7b significantly inhibited H37Rv induced production of IL-6 and tumor necorsis factor (TNF) alpha as well as cell death of peritoneal macrophages. These findings suggest that IL-1F7b be an important regulator of Mtb infection. Therefore, here we will explore the functional role of IL-1F7b in the process of Mtb infection of host macrophages and pathogenesis of tuberculosis by combining utilization of macrophage and mouse infection model as well as clinical samples analysis, and clarify the underlying modulation mechanism. This research will finally provide novel molecular target and intervention for the prevention and treatment of tuberculosis.

结核菌感染及致病过程中重要的免疫调节因子的鉴定和分析对于理解结核病的发病机制、开发新的干预和治疗手段十分重要。IL-1F7b是IL-1家族中重要的抑制性细胞因子，可抑制天然免疫应答。但是，IL-1F7b在结核菌感染过程中的作用还未见报道。我们初步研究发现：（1）IL-1F7b基因的rs6717710 C/T和rs3811047 A/G 2个SNP位点多态性与结核病的发生紧密相关；（2）IL-1F7b能显著抑制巨噬细胞经感染结核菌H37Rv后释放的细胞因子IL-6与TNF-α；（3）IL-1F7b能显著抑制H37Rv诱导的巨噬细胞死亡。以上研究结果提示IL-1F7b可能参与调节结核菌的感染过程，为此，本项目将进一步从分子水平，细胞水平、动物感染模型及临床样本分析等不同层次，研究IL-1F7b在结核菌感染及致病过程中的功能及作用机制，为结核病的预防与治疗提供新的理论基础。

宿主的免疫应答对限制结核病的发生及发展至关重要，筛选影响结核菌感染过程中具有重要调节作用的宿主免疫调节因子对于理解结核病的发病机制，开发新的分子靶标及相应的治疗手段十分重要。本项目研究发现抑制性细胞因子IL-37基因的单核苷酸多态性与结核病易感性相关，其在结核病人外周血血清中表达水平显著上调。IL-37可以显著抑制结核菌诱导的细胞因子包括TNF-α和IL-6，并抑制结核菌诱导的相关信号通路如MAPK、NF-κB信号通路。研究发现IL-37可能通过与蛋白酪氨酸磷酸酶SHP-1相互作用发挥抑炎功能。通过构建IL-37转基因小鼠及BCG鼻腔感染模型发现IL-37对结核菌感染小鼠具有保护性。IL-37转基因小鼠感染后较野生型小鼠细菌负荷显著降低，肺部病理损伤明显减轻。其中脾脏Th1细胞比率显著上调，提示IL-37可能通过影响Th1细胞进而调控结核病发病过程。该研究提示IL-37可能作为结核病诊断与治疗的潜在分子靶标。