Silva J S, Twardzik D R, Reed S G
Seattle Biomedical Research Institute, Washington 98109.
J Exp Med. 1991 Sep 1;174(3):539-45. doi: 10.1084/jem.174.3.539.
The effects of transforming growth factor beta (TGF-beta) on interferon gamma-mediated killing of the intracellular protozoan parasite Trypanosoma cruzi and on the course of T. cruzi infection in mice were investigated. Spleen cells from mice with acute T. cruzi infections were found to produce elevated levels of biologically active TGF-beta in vitro, and the possibility that TGF-beta may mediate certain aspects of T. cruzi infection was then addressed. When mouse peritoneal macrophages were treated with TGF-beta in vitro, the ability of IFN-gamma to activate intracellular inhibition of the parasite was blocked. This occurred whether cells were treated with TGF-beta either before or after IFN-gamma treatment. TGF-beta treatment also blocked the T. cruzi-inhibiting effects of IGN-gamma on human macrophages. Additionally, treatment of human macrophages with TGF-beta alone led to increased parasite replication in these cells. The effects of TGF-beta on T. cruzi infection in vivo were then investigated. Susceptible C57BL/6 mice developed higher parasitemias and died earlier when treated with TGF-beta during the course of infection. Resistant C57BL/6 x DBA/2 F1 mice treated with TGF-beta also had increased parasitemias, and 50% mortality, compared with no mortality in infected, saline-treated controls. A single dose of TGF-beta, given at the time of infection, was sufficient to significantly decrease resistance to infection in F1 mice and to exacerbate infection in susceptible C57BL/6 mice. Furthermore, a single injection of TGF-beta was sufficient to counter the in vivo protective effects of IFN-gamma. We conclude that TGF-beta, produced during acute T. cruzi infection in mice, is a potent inhibitor of the effects of macrophage activating cytokines in vivo and in vitro and may play a role in regulating infection.
研究了转化生长因子β（TGF-β）对干扰素γ介导的细胞内原生动物寄生虫克氏锥虫杀伤作用以及对小鼠克氏锥虫感染进程的影响。发现急性克氏锥虫感染小鼠的脾细胞在体外产生的生物活性TGF-β水平升高，随后探讨了TGF-β可能介导克氏锥虫感染某些方面的可能性。当小鼠腹腔巨噬细胞在体外接受TGF-β处理时，IFN-γ激活细胞内抑制寄生虫的能力被阻断。无论细胞在IFN-γ处理之前还是之后接受TGF-β处理，均会出现这种情况。TGF-β处理还阻断了IGN-γ对人巨噬细胞的克氏锥虫抑制作用。此外，单独用TGF-β处理人巨噬细胞会导致这些细胞内寄生虫复制增加。随后研究了TGF-β对体内克氏锥虫感染的影响。在感染过程中接受TGF-β处理的易感C57BL/6小鼠出现更高的寄生虫血症且死亡更早。与感染后用生理盐水处理的对照组无死亡相比，接受TGF-β处理的抗性C57BL/6×DBA/2 F1小鼠也有更高的寄生虫血症和50%的死亡率。在感染时给予单剂量的TGF-β足以显著降低F1小鼠对感染的抵抗力，并加剧易感C57BL/6小鼠的感染。此外，单次注射TGF-β足以抵消IFN-γ的体内保护作用。我们得出结论，小鼠急性克氏锥虫感染期间产生的TGF-β是体内和体外巨噬细胞激活细胞因子作用的有效抑制剂，可能在调节感染中发挥作用。
