Castaños-Velez E, Maerlan S, Osorio L M, Aberg F, Biberfeld P, Orn A, Rottenberg M E
Department of Pathology, Karolinska Institute, Stockholm, Sweden.
Infect Immun. 1998 Jun;66(6):2960-8. doi: 10.1128/IAI.66.6.2960-2968.1998.
Tumor necrosis factor receptor p55 (TNFRp55) mediates host resistance to several pathogens by allowing microbicidal activities of phagocytes. In the studies reported here, TNFRp55-/- mice infected with the intracellular parasite Trypanosoma cruzi showed clearly higher parasitemia and cumulative mortality than wild-type (WT) controls did. However, gamma interferon (IFN-gamma)-activated macrophages from TNFRp55-/- mice produced control levels of nitric oxide and killed the parasite efficiently in vitro. Trypanocidal mechanisms of nonphagocytic cells (myocardial fibroblasts) from both TNFRp55-/- and WT mice were also activated by IFN-gamma in a dose-dependent way. However, IFN-gamma-activated TNFRp55-/- nonphagocytes showed less effective killing of T. cruzi than WT control nonphagocytes, even when interleukin 1beta (IL-1beta) was added as a costimulator. In vivo, T. cruzi-infected TNFRp55-/- mice and WT mice released similar levels of NO and showed similar levels of IFN-gamma mRNA and inducible nitric oxide synthase mRNA in their tissues. Instead, increased susceptibility to T. cruzi of TNFRp55-/- mice was associated with reduced levels of parasite-specific immunoglobulin G (IgG) (but not IgM) antibodies during infection, which is probably linked to abnormal B-cell differentiation in secondary lymphoid tissues of the mutant mice. Surprisingly, T. cruzi-infected TNFRp55-/- mice showed increased inflammatory and necrotic lesions in several tissues, especially in skeletal muscles, indicating that TNFRp55 plays an important role in controlling the inflammatory process. Accordingly, levels of Mn2+ superoxide dismutase mRNA, a TNF-induced enzyme which protects the cell from the toxic effects of superoxide, were lower in mutant than in WT infected mice.
肿瘤坏死因子受体p55（TNFRp55）通过允许吞噬细胞的杀菌活性来介导宿主对多种病原体的抵抗力。在本研究中，感染细胞内寄生虫克氏锥虫的TNFRp55基因敲除小鼠的寄生虫血症和累积死亡率明显高于野生型（WT）对照小鼠。然而，来自TNFRp55基因敲除小鼠的γ干扰素（IFN-γ）激活的巨噬细胞产生的一氧化氮水平正常，并在体外有效杀死了寄生虫。来自TNFRp55基因敲除小鼠和野生型小鼠的非吞噬细胞（心肌成纤维细胞）的杀锥虫机制也以剂量依赖的方式被IFN-γ激活。然而，即使添加白细胞介素1β（IL-1β）作为共刺激因子，IFN-γ激活的TNFRp55基因敲除的非吞噬细胞对克氏锥虫的杀伤效果也不如野生型对照非吞噬细胞。在体内，感染克氏锥虫的TNFRp55基因敲除小鼠和野生型小鼠释放的一氧化氮水平相似，并且在其组织中显示出相似水平的IFN-γ mRNA和诱导型一氧化氮合酶mRNA。相反，TNFRp55基因敲除小鼠对克氏锥虫易感性增加与感染期间寄生虫特异性免疫球蛋白G（IgG）（而非IgM）抗体水平降低有关，这可能与突变小鼠次级淋巴组织中B细胞分化异常有关。令人惊讶的是，感染克氏锥虫的TNFRp55基因敲除小鼠在多个组织中，尤其是骨骼肌中，出现了炎症和坏死性病变增加的情况，这表明TNFRp55在控制炎症过程中起重要作用。因此，突变小鼠中Mn2+超氧化物歧化酶mRNA的水平低于野生型感染小鼠，Mn2+超氧化物歧化酶是一种TNF诱导的酶，可保护细胞免受超氧化物的毒性作用。
