期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2004
卷号：101
期号：13
页码：4560-4565
DOI：10.1073/pnas.0400983101
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Macrophages (M{varphi}) play a central role as effector cells in immunity to intracellular pathogens such as Mycobacterium. Paradoxically, they also provide a habitat for intracellular bacterial survival. This paradoxical role of M{varphi} remains poorly understood. Here we report that this dual role may emanate from the functional plasticity of M{varphi}: Whereas M{varphi}-1 polarized in the presence of granulocyte-M{varphi} colony-stimulating factor promoted type 1 immunity, M{varphi}-2 polarized with M{varphi} colony-stimulating factor subverted type 1 immunity and thus may promote immune escape and chronic infection. Importantly, M{varphi}-1 secreted high levels of IL-23 (p40/p19) but no IL-12 (p40/p35) after (myco)bacterial activation. In contrast, activated M{varphi}-2 produced neither IL-23 nor IL-12 but predominantly secreted IL-10. M{varphi}-1 required IFN-{gamma} as a secondary signal to induce IL-12p35 gene transcription and IL-12 secretion. Activated dendritic cells produced both IL-12 and IL-23, but unlike M{varphi}-1 they slightly reduced their IL-23 secretion after addition of IFN-{gamma}. Binding, uptake, and outgrowth of a mycobacterial reporter strain was supported by both M{varphi} subsets, but more efficiently by M{varphi}-2 than M{varphi}-1. Whereas M{varphi}-1 efficiently stimulated type 1 helper cells, M{varphi}-2 only poorly supported type 1 helper function. Accordingly, activated M{varphi}-2 but not M{varphi}-1 down-modulated their antigen-presenting and costimulatory molecules (HLA-DR, CD86, and CD40). These findings indicate that (i)M{varphi}-1 and M{varphi}-2 play opposing roles in cellular immunity and (ii) IL-23 rather than IL-12 is the primary type 1 cytokine produced by activated proinflammatory M{varphi}-1. M{varphi} heterogeneity thus may be an important determinant of immunity and disease outcome in intracellular bacterial infection.
