Nelson B J, Ralph P, Green S J, Nacy C A
Department of Cellular Immunology, Walter Reed Army Institute of Research, Washington, DC 20307-5100.
J Immunol. 1991 Mar 15;146(6):1849-57.
We examined the effects of TGF-beta 1 on induction of several activated macrophage antimicrobial activities against the protozoan parasite Leishmania, and on induction of tumoricidal activity against the fibrosarcoma tumor target 1023. TGF-beta by itself did not affect the viability of either the intracellular or extracellular target in concentrations up to 200 ng/ml. As little as 1 ng/ml TGF-beta, however, suppressed more than 70% of the intracellular killing activity of macrophages treated with lymphokines. In contrast, more than 100 ng/ml TGF-beta was required to suppress intracellular killing by cells activated with an equivalent amount of recombinant IFN-gamma. Addition of TGF-beta for up to 30 min after exposure to activation factors significantly reduced macrophage killing of intracellular parasites. Pretreatment of macrophages with TGF-beta was even more effective: treatment of cells with TGF-beta for 4 h before addition of activation factors abolished all macrophage intracellular killing activity. Regardless of treatment sequence, however, TGF-beta had absolutely no effect, at any concentration tested, on activated macrophage resistance to infection induced by lymphokines or by the cooperative interaction of IFN-gamma and IL-4. Effects of TGF-beta on tumoricidal activity of activated macrophages was intermediate to that of its effects on intracellular killing or resistance to infection. Lymphokine-induced tumor cytotoxicity was marginally (25%) affected by TGF-beta; 200 ng/ml was able to suppress IFN-gamma-induced tumoricidal activity by 40%. Thus, TGF-beta dramatically suppressed certain activated macrophage cytotoxic effector reactions, but was only partially or not at all effective against others, even when the same activation agent (IFN-gamma) was used. The biochemical target for TGF-beta suppressive activity in these reactions may be the pathway for nitric oxide production from L-arginine, because TGF-beta also inhibited the generation of nitric oxide by cytokine-activated macrophages.
我们研究了转化生长因子β1（TGF-β1）对诱导巨噬细胞针对原生动物寄生虫利什曼原虫的多种活化抗菌活性，以及对诱导巨噬细胞针对纤维肉瘤肿瘤靶标1023的杀肿瘤活性的影响。在浓度高达200 ng/ml时，TGF-β本身对细胞内或细胞外靶标的活力均无影响。然而，低至1 ng/ml的TGF-β就能抑制经淋巴因子处理的巨噬细胞70%以上的细胞内杀伤活性。相比之下，需要超过100 ng/ml的TGF-β才能抑制等量重组干扰素-γ（IFN-γ）激活的细胞的细胞内杀伤作用。在接触激活因子后添加TGF-β长达30分钟，可显著降低巨噬细胞对细胞内寄生虫的杀伤作用。用TGF-β预处理巨噬细胞效果更佳：在添加激活因子前用TGF-β处理细胞4小时，可消除所有巨噬细胞的细胞内杀伤活性。然而，无论处理顺序如何，在任何测试浓度下，TGF-β对经淋巴因子或IFN-γ与白细胞介素-4（IL-4）协同作用诱导激活的巨噬细胞抗感染能力均无影响。TGF-β对激活巨噬细胞杀肿瘤活性的影响介于其对细胞内杀伤或抗感染能力的影响之间。淋巴因子诱导的肿瘤细胞毒性受到TGF-β的轻微（25%）影响；200 ng/ml的TGF-β能够抑制IFN-γ诱导的杀肿瘤活性达40%。因此，TGF-β显著抑制了某些激活巨噬细胞的细胞毒性效应反应，但对其他反应仅部分有效或完全无效，即使使用相同的激活剂（IFN-γ）也是如此。在这些反应中，TGF-β抑制活性的生化靶点可能是由L-精氨酸生成一氧化氮的途径，因为TGF-β也抑制细胞因子激活的巨噬细胞产生一氧化氮。
