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Role of endogenous IFN-gamma in macrophage programming induced by IL-12 and IL-18.
- Source :
-
Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research [J Interferon Cytokine Res] 2007 May; Vol. 27 (5), pp. 399-410. - Publication Year :
- 2007
-
Abstract
- Besides the established role of interleukin-12 (IL-12) and IL-18 on interferon-gamma (IFN-gamma) 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-alpha (TNF-alpha) production by CD11b(+) adherent peritoneal cells, focusing on the involvement of endogenously produced IFN-gamma. C57BL/6 cells released substantial amounts of NO when stimulated with IFN-gamma 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-alpha 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-gamma, IFNGR, and IFN regulatory factor-1 (IRF-1) revealed that these molecules were essential for LPS-induced NO release, but TNF-alpha production was IFN-gamma independent. Conversely, the myeloid differentiation factor 88 (MyD88)-dependent pathway was indispensable for IL-12/IL-18-programmed LPS-induced TNF-alpha 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-gamma secretion. Nevertheless, a small population of IFN-gamma(+) 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-gamma. 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-gamma plays an important role in programming the NO response, whereas the TNF-alpha response occurs through an IFN-gamma-independent pathway.
- Subjects :
- Animals
CD11b Antigen immunology
Drug Synergism
Interferon Regulatory Factor-1 physiology
Interferon-gamma genetics
Interferon-gamma metabolism
Interferon-gamma pharmacology
Lipopolysaccharides pharmacology
Macrophage Activation
Macrophages, Peritoneal immunology
Macrophages, Peritoneal parasitology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Myeloid Differentiation Factor 88 metabolism
Nitric Oxide biosynthesis
Recombinant Proteins
Trypanosoma cruzi immunology
Trypanosoma cruzi parasitology
Tumor Necrosis Factor-alpha biosynthesis
Interferon-gamma physiology
Interleukin-12 pharmacology
Interleukin-18 pharmacology
Macrophages, Peritoneal drug effects
Macrophages, Peritoneal metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1079-9907
- Volume :
- 27
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research
- Publication Type :
- Academic Journal
- Accession number :
- 17523872
- Full Text :
- https://doi.org/10.1089/jir.2007.0128