Study on the roles of immunosuppressive cytokines in the establishment and progression of mycobacterial infections

本研究探讨了IL-10和TGF-β等免疫抑制细胞因子在小鼠非典型分枝杆菌复合体（MAC）感染部位细菌再生长的启动和进展中的作用，免疫抑制巨噬细胞（Mphis）诱导的相对早期阶段（2至3周）在建立持续MAC感染小鼠在宿主小鼠中的作用。获得了以下结果。(1)在MAC感染中，其中细菌再生长在感染后第2至4周开始，肺和脾中TNF-α、IL-10和IFN-γ的组织水平在第2至4周左右暂时升高，而脾中的TGF-β水平在第4至8周期间保持高水平。细胞因子水平的瞬时增加被宿主小鼠的利福霉素治疗阻断。(2)当小鼠腹膜或脾Mphis感染MAC生物体时， ...更多信息 s，在前3天培养期间观察到TNF-α、IL-6和IL-10的Mphi产生的增加，而在培养的更晚阶段例如在第7至14天期间观察到TGF-β产生。在用MAC刺激Mphi后2至6 h期间观察编码这些细胞因子的mRNA的表达。(3)发现TNF-α和IFN-γ参与MAC感染小鼠中免疫抑制性Mphis的体内诱导，并通过增强某些效应分子（包括前列腺素E、活性氮中间体和磷脂）的Mphi产生，在其针对T细胞有丝分裂的抑制功能的表达中发挥重要作用。(4)使用抗IL-10和抗TGF-β抗体的阻断实验表明，在开始Mphi培养后的第1至3天期间观察到的MAC感染的Mphis中TNF-α介导的粘附分子ICAM-1的表达被Mphis自身以自分泌方式产生的IL-10和TGF-β下调。这些发现表明免疫抑制细胞因子在宿主MAC感染的进展中起重要作用。少

This study has deatl with the roles of immunosuppressive cytokines including IL-10 and TGF-beta in the initiation and the progression of bacterial regrowth at the sites of infection due to Mycobacterium avium complex (MAC), one of the representative atypical mycobacteria, induced in mice and, moreover, the roles of immunosuppressor macrophages (Mphis) induced in the relatively early phase (weeks 2 to 3) of infection in the establishment of persistent MAC infected mice in host mice. The following results were obtained. (1) In MAC infection in which the bacterial regrowth was initiated from weeks 2 to 4 after infection, the tissue levels of TNF-alpha, IL-10, and IFN-gamma in the lungs and spleens were temporarily elevated around weeks 2 to 4, while the TGF-beta levels in the spleen remained high during weeks 4 to 8. The transient increase in the cytokine levels was blocked by rifamycin-treatment of host mice. (2) When murine peritoneal or splenic Mphis were infected with the MAC organism … More s, the increase in Mphi production of TNF-alpha, IL-6, and IL-10 was seen during the first 3-day cultivation, whereas TGF-beta production was observed in much later phase of cultivation such as during days 7 to 14. The expression of mRNA encoding these cytokines was observed during 2 to 6 h after Mphi stimulation with the MAC.(3) TNF-alpha and IFN-gamma were found to participate in the in-vivo induction of the immunosuppressive Mphis in MAC-infected mice and play an important role in the experssion of their suppressor function against T cell mitogenesis, by enhancing Mphi production of certain effector molecules including prostaglandin E,reactive nitrogen intermediates, and phospholipids. (4) The blocking experiments using anti-IL-10 and anti-TGF-beta antibodies showed that the TNF-alpha-mediated expression of an adhesion molecule ICAM-1 in MAC-infected Mphis observed during days 1 to 3 after the initiation of Mphi cultivation was down-regulated by IL-10 and TGF-beta produced by the Mphis themselves in an autocrine fashion. These findings indicate important roles of immunosuppressive cytokines in progression of MAC infection in hosts. Less