Alberati-Giani D, Malherbe P, Ricciardi-Castagnoli P, Köhler C, Denis-Donini S, Cesura A M
Pharma Division, Preclinical Research, Nervous System Diseases, F. Hoffmann La Roche Ltd., Basel, Switzerland.
J Immunol. 1997 Jul 1;159(1):419-26.
Induction of indoleamine 2,3-dioxygenase (IDO) and nitric oxide synthase (NOS) is involved in the immunomodulatory roles of IFN-gamma and evidence suggests that these pathways are functionally cross-regulated. We report here that nitric oxide (NO) negatively modulates the expression of IDO activity in IFN-gamma-primed macrophages, but not in microglial cells from mouse. In MT2 macrophages, the induction of IDO activity by IFN-gamma was further increased by the presence of NOS inhibitors, whereas culturing of IFN-gamma-activated MT2 cells with NO generators produced a marked reduction of IDO activity expression. Conversely, neither NOS inhibitors nor exogenous NO affected the induction of the enzyme activity in N11 microglial cells after IFN-gamma activation. LPS and picolinic acid, two costimulatory agents that up-regulate inducible NOS in activated cells, regulated IDO induction differently in the two cell lines. LPS and picolinic acid caused a significant decrease of IDO activity in IFN-gamma-activated MT2 cells. This effect, however, did not appear to be mediated by the ability of LPS and picolinic acid to stimulate NO production. In N11 cells, LPS further stimulated the enzyme activity and picolinic acid had no effect. Northern blot analysis revealed that, in MT2 macrophages, NOS inhibitors increased the levels of IDO mRNA, while a reduction was observed with picolinic acid. No changes in IDO mRNA levels were detected in N11 cells. Consistent with the functional heterogeneity of phagocytes, the reported results indicate the existence of marked differences in the regulation of IDO expression between murine macrophages and microglial cells.
吲哚胺2,3-双加氧酶（IDO）和一氧化氮合酶（NOS）的诱导参与了γ-干扰素的免疫调节作用，并且有证据表明这些途径在功能上是交叉调节的。我们在此报告，一氧化氮（NO）对γ-干扰素预处理的巨噬细胞中IDO活性的表达具有负调节作用，但对小鼠小胶质细胞则无此作用。在MT2巨噬细胞中，NOS抑制剂的存在进一步增强了γ-干扰素对IDO活性的诱导作用，而用NO生成剂培养γ-干扰素激活的MT2细胞则使IDO活性表达显著降低。相反，在γ-干扰素激活后，NOS抑制剂和外源性NO均不影响N11小胶质细胞中该酶活性的诱导。脂多糖（LPS）和吡啶甲酸是两种在活化细胞中上调诱导型NOS的共刺激剂，它们对两种细胞系中IDO诱导的调节作用不同。LPS和吡啶甲酸使γ-干扰素激活的MT2细胞中IDO活性显著降低。然而，这种作用似乎不是由LPS和吡啶甲酸刺激NO生成的能力介导的。在N11细胞中，LPS进一步刺激了该酶的活性，而吡啶甲酸则无作用。Northern印迹分析显示，在MT2巨噬细胞中，NOS抑制剂增加了IDO mRNA的水平，而吡啶甲酸则使其降低。在N11细胞中未检测到IDO mRNA水平的变化。与吞噬细胞的功能异质性一致，所报道的结果表明，小鼠巨噬细胞和小胶质细胞在IDO表达调节方面存在显著差异。
