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

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.

Interleukin-12p35 Deletion Promotes CD4 T-Cell–Dependent Macrophage Differentiation and Enhances Angiotensin II–Induced Cardiac Fibrosis

“…8 The primary effect of IL-12 is to stimulate naïve T cells (TCs) to differentiate into Th1 cells, but IL-12 may also be a key controller of the macrophage phenotype in certain infected conditions. [9][10][11] For example, IL-12 pretreatment can program macrophages to release more tumor necrosis factor-α and NO in the presence of LPS or Trypanosoma cruzi infection. 11 Moreover, IL-12p40-deficient macrophages are biased toward an M2 macrophage profile.…”

“…[9][10][11] For example, IL-12 pretreatment can program macrophages to release more tumor necrosis factor-α and NO in the presence of LPS or Trypanosoma cruzi infection. 11 Moreover, IL-12p40-deficient macrophages are biased toward an M2 macrophage profile. 9 IL-12-deficient DCs show increased levels of M2-associated genes and reduced levels of M1-associated genes in response to LPS.…”

Dysregulation of Serum Gamma Interferon Levels in Vascular Chronic Q Fever Patients Provides Insights into Disease Pathogenesis

“…Thus, it appears that although one of the cytokines involved in activation of IFN-␥ production was present, this did not result in IFN-␥ production in vascular chronic Q fever patients, whereas acute patients readily produced IFN-␥. In addition to IL-18, also IL-12p70, which is known to induce the production of IFN-␥ by NK cells and T cells (26), and IL-23, another cytokine involved in the Th1 immune response by activating inflammatory cells that is required for induction of chronic inflammation and granuloma formation (27), were measured in the initial biomarker panel. The latter did not show any signs of differential expression among the three patient groups.…”

Parasite-Derived Neurotrophic Factor/trans-Sialidase of Trypanosoma cruzi Links Neurotrophic Signaling to Cardiac Innate Immune Response

“…During the initial stage of infection, members of the Toll-like receptor (TLR) family of pattern recognition proteins play an important role in T. cruzi recognition, as they are activated by parasite molecules, such as DNA, RNA, or glycosylphosphatidylinositol (GPI) anchors, initiating a signaling cascade dependent on the adaptor molecule myeloid differentiation factor 88 (MyD88), which mediates upregulation of proinflammatory genes pivotal to the resistance to T. cruzi infection. In addition, T. cruzi activates Nod1 and inflammasome (NLRP3) proinflammatory pathways, and the end result is an increase in the levels of interleukin-1␤ (IL-1␤) (7), IL-6 (7,8), IL-12 (9-13), tumor necrosis factor alpha (10,(12)(13)(14), beta interferon (IFN-␤) and IFN-␥ (7,12,13,(15)(16)(17), and monocyte chemoattractant protein 1 (MCP-1)/CCL2 and other chemokines essential to the recruitment of inflammatory cells to infection sites (18,19).…”