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Role of Endogenous IFN-γ in Macrophage Programming Induced by IL-12 and IL-18

2007; Mary Ann Liebert, Inc.; Volume: 27; Issue: 5 Linguagem: Inglês

10.1089/jir.2007.0128

1557-7465

Karina R. B. Bastos, Renato Barboza, Luiz Roberto Sardinha, Momtchilo Russo, José María Álvarez, Maria Regina D’Império Lima,

Immune Cell Function and Interaction

Besides the established role of interleukin-12 (IL-12) and IL-18 on interferon-γ (IFN-γ) production by natural killer (NK), T, and B cells, the effects of these cytokines on macrophages are largely unknown. Here, we investigated the role of IL-12/IL-18 on nitric oxide (NO) and tumor necrosis factor-α (TNF-α) production by CD11b+ adherent peritoneal cells, focusing on the involvement of endogenously produced IFN-γ. C57BL/6 cells released substantial amounts of NO when stimulated with IFN-γ or lipopolysaccharide (LPS), but failed to respond to IL-12 or IL-18 or both. However, IL-12/IL-18 pretreatment was able to program these cells to release 6–8-fold more NO and TNF-α in response to LPS or Trypanosoma cruzi stimulation, with NO levels directly correlating with macrophage resistance to intracellular parasite growth. Analysis of IL-12/IL-18-primed cells from mice deficient in IFN-γ, IFNGR, and IFN regulatory factor-1 (IRF-1) revealed that these molecules were essential for LPS-induced NO release, but TNF-α production was IFN-γ independent. Conversely, the myeloid differentiation factor 88 (MyD88)-dependent pathway was indispensable for IL-12/IL-18-programmed LPS-induced TNF-α production, but not for NO release. Contaminant T and NK cells largely modulated the IL-12/IL-18 programming of LPS-induced NO response through IFN-γ secretion. Nevertheless, a small population of IFN-γ+ cells with a macrophage phenotype was also identified, particularly in the peritoneum of chronically T. cruzi-infected mice, reinforcing the notion that macrophages can be an alternative source of IFN-γ. Taken together, our data contribute to elucidate the molecular basis of the IL-12/IL-18 autocrine pathway of macrophage activation, showing that endogenous IFN-γ plays an important role in programming the NO response, whereas the TNF-α response occurs through an IFN-γ-independent pathway.