Aliberti J C, Cardoso M A, Martins G A, Gazzinelli R T, Vieira L Q, Silva J S
Department of Immunology, School of Medicine of Ribeirão Preto, SP, Brazil.
Infect Immun. 1996 Jun;64(6):1961-7. doi: 10.1128/iai.64.6.1961-1967.1996.
Host resistance to infection by Trypanosoma cruzi is dependent on both natural and acquired immune responses. During the first week of infection in mice, NK cell-derived gamma interferon (IFN-gamma) is involved in controlling intracellular parasite replication, mainly through the induction of NO biosynthesis by activated macrophages. Interleukin-12 (IL-12) has been shown to be a powerful cytokine in inducing IFN-gamma synthesis by NK cells, as well as in mediating resistance to different intracellular protozoa. We have therefore studied the ability of T. cruzi to elicit IL-12 synthesis by macrophages and the role of this cytokine in controlling parasite replication during acute infection in mice. Our results show that macrophages cultured in the presence of live trypomastigote forms (but not epimastigotes) release IL-12 that can induce IFN-gamma production by normal spleen cells. IL-12 was detected in as little as 12 h after the addition of the trypomastigotes, and the level of IL-12 peaked at 48 h after the initial macrophage-parasite incubation. The addition of anti-IL-12 monoclonal antibody to macrophage-trypomastigote supernatants dose-dependently inhibited IFN-gamma production by naive splenocytes. Finally, the in vivo role of IL-12 in resistance to infection by T. cruzi was analyzed. Mice treated with anti-IL-12 monoclonal antibody had significantly increased parasitemia and mortality in comparison with those of control infected mice treated with control antibody. Together, these results suggest that macrophage-derived IL-12 plays a major role in controlling the parasitemia in T. cruzi-infected mice and that the animal's resistance during the acute phase of infection may, at least in part, be a consequence of postinfection levels of IL-12.
宿主对克氏锥虫感染的抵抗力取决于天然免疫和获得性免疫反应。在小鼠感染的第一周，自然杀伤细胞（NK细胞）产生的γ干扰素（IFN-γ）参与控制细胞内寄生虫的复制，主要是通过激活巨噬细胞诱导一氧化氮（NO）的生物合成来实现。白细胞介素-12（IL-12）已被证明是一种强大的细胞因子，可诱导NK细胞合成IFN-γ，以及介导对不同细胞内原生动物的抵抗力。因此，我们研究了克氏锥虫诱导巨噬细胞合成IL-12的能力，以及这种细胞因子在小鼠急性感染期间控制寄生虫复制中的作用。我们的结果表明，在活的锥鞭毛体形式（而非无鞭毛体）存在的情况下培养的巨噬细胞会释放IL-12，IL-12可诱导正常脾细胞产生IFN-γ。在加入锥鞭毛体后仅12小时就能检测到IL-12，并且在巨噬细胞与寄生虫最初孵育后的第48小时，IL-12水平达到峰值。向巨噬细胞-锥鞭毛体上清液中加入抗IL-12单克隆抗体，可剂量依赖性地抑制未接触过抗原的脾细胞产生IFN-γ。最后，分析了IL-12在体内对克氏锥虫感染抵抗力中的作用。与用对照抗体处理的对照感染小鼠相比，用抗IL-12单克隆抗体处理的小鼠的寄生虫血症和死亡率显著增加。总之，这些结果表明，巨噬细胞来源的IL-12在控制克氏锥虫感染小鼠的寄生虫血症中起主要作用，并且动物在感染急性期的抵抗力可能至少部分是感染后IL-12水平的结果。
