IFN‐γ enhances bovine macrophage responsiveness to Mycobacterium bovis: Impact on bacterial replication, cytokine release and macrophage apoptosis

Abstract

Summary We sought to determine the impact of bovine IFN-γ on the interaction between Mycobacterium bovis and bovine macrophages. Bovine macrophages released small amounts of nitric oxide (NO), TNF-α , IL-1 β and IL-12 upon infection with bacille Calmette-Guérin (BCG). Prior pulsing of cells with IFN-γ significantly enhanced the release of NO and IL-12. Infection of bovine macrophages with virulent M. bovis led to the release of higher levels of pro-inflammatory mediators, compared to levels released upon BCG infection. IFN-γ treatment of macrophages enhanced the release of pro-inflammatory mediators, but did not modify bacterial replication in M. bovis -infected macrophages. Treatment of macrophages with a combination of IFN-γ and LPS led to a reduction in bacterial replication. Infected cells treated with IFN-γ /LPS progressed mostly through an apoptotic pathway, whereas untreated infected cells eventually died by necrosis. Agents that prevented the acquisition of bacteriostatic activity by activated macrophages also prevented the induction of apoptosis in infected macrophages (IL-10 and neutralizing anti-TNF-α ). We conclude that virulent M. bovis is a major determinant of release of pro-inflammatory cytokines by macrophages. IFN-γ amplifies the macrophage cytokine release in response to M. bovis . Induction of apoptosis is closely linked to the emergence of macrophage resistance to M. bovis replication, which is dependent on endogenous TNF-α release.

Synthetic Lipopeptide MALP-2 Inhibits Intracellular Growth of Mycobacterium bovis BCG in Alveolar Macrophages—Preliminary Data

“…In contrast 7 days after infection the stimulation of macrophages with IFN-γ had inconsistent effects on M. bovis BCG replication. This observation was also described by Denis et al [13], who reported that addition of IFN-γ had variable effects on M. bovis BCG replication in macrophages. We could exclude that a decrease of cell numbers was responsible for this effect.…”

“…bovis BCG strain Pasteur was used in all experiments [12,13]. The strain was grown to mid log phase in Middlebrook 7H9 media (BD Difco) supplemented with 10% albumin-dextrose, 1% glycerol and 0.05% Tween 80 at 37°C.…”

Immunomodulatory effects of recombinant BCG expressing MSP-1C ofPlasmodium falciparumon LPS- or LPS+IFN-γ-stimulated J774A.1 cells

“…These results also consistent with several other studies showing that BCG stimulates the production of TNF-α and IL-1β by macrophages, [73][74][75] and the stimulation is enhanced in the presence of LPS 73 and further enhanced with the presence of LPS+IFN-γ. 76,77 We also demonstrated that phagocytosis of the BCG and rBCG strains not only reduced the viability of the macrophages but also resulted in a substantial reduction in replication of the mycobacteria. These reductions were significantly greater in macrophages infected with rBCG than those of the parent BCG.…”

Reduced apoptosis and increased inflammatory cytokines in granulomas caused by tuberculous compared to non-tuberculous mycobacteria: role of MPT64 antigen in apoptosis and immune response

“…On the other hand, IL-10 expression has been shown to be associated with increased cell survival and inhibition of apoptosis [12,13]. Interferon (IFN)-g has been shown to enhance the lipopolysaccharide-induced apoptosis of alveolar macrophages [13,14]. Transforming growth factor (TGF)-b is involved both in the induction [15,16] and inhibition of apoptosis [17].…”