Involvement of reactive oxygen intermediates in tumor necrosis factor alpha-dependent bacteriostasis of Mycobacterium avium

Abstract

We studied the involvement of reactive oxygen intermediates and reactive nitrogen intermediates in the bacteriostasis of two Mycobacterium avium strains differing in virulence by resident peritoneal macrophages. We found that both the highly virulent strain (25291) and the low-virulence strain (1983) of M. avium induced superoxide production but inhibited nitrite production in vitro. This inhibition was due to the production of superoxide, a nitric oxide scavenger. The stimulation of superoxide production was two-to fivefold higher in strain 1983-infected than in strain 25291-infected resident peritoneal macrophages and was independent of contaminating T cells or NK cells. Superoxide secretion was dependent on the tumor necrosis factor (TNF) produced endogenously by the macrophages. This was also true when macrophages were isolated from infected mice. Addition of TNF to the infected resident peritoneal macrophages caused only a slight, albeit significant, increase in superoxide production by strain 25291-infected macrophages. Incubation of resident peritoneal macrophages with different scavengers of reactive oxygen intermediates showed that strain 1983 was susceptible to hydrogen peroxide produced by resident peritoneal macrophages. Strain 25291 was shown to decrease superoxide secretion inside heavily infected bone marrow-derived macrophages. This strain was also shown to be a better trigger for production of reactive oxygen intermediates than strain 1983. In summary, strain 1983 induced high levels of TNF synthesis that acted in an autocrine fashion to stimulate production of reactive oxygen intermediates by macrophages leading to growth restriction mediated by hydrogen peroxide. The highly virulent strain 25291 induced low levels of TNF synthesis, and therefore little reactive oxygen intermediate production, and could also inhibit superoxide production by the infected macrophages.

The modulating effects of proinflammatory cytokines interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α), and immunoregulating cytokines IL-10 and transforming growth factor-beta (TGF-β), on anti-microbial activity of murine peritoneal macrophages againstMycobacterium avium-intracellularecomplex

“…First, both IFN-g and TNF-a caused significant inhibition of the growth of MAIC organisms in macrophages (Figs 1 and 2). This finding is consistent with the majority of previous observations, although, the effectiveness of IFN-g and TNF-a in promoting macrophage anti-MAIC functions, observed here, were not so great as reported [7,8,10,[14][15][16]. The present study also showed that the efficacy of IFN-g in promoting the macrophage activity was greater than that of TNF-a.…”

“…Second, TNF-a is widely known to up-regulate macrophage microbicidal activity against mycobacteria [3,5,6,10,12]. TNF-amediated potentiation of macrophage anti-MAIC activity has been observed for mouse peritoneal macrophages [10,13,14], human monocytes [15], and human monocyte-derived macrophages [13,16]. However, a recent study by Bermudez et al [17] revealed that entry of MAIC organisms into macrophages by alternate receptors other than complement and mannose receptors was associated with resistance to TNF-a-induced bactericidal mechanisms of human monocyte-derived macrophages.…”

Induction of cvtokines and expression of surface receptors in Mono Mac 6 cells after infection with different Legionella species

“…Early elevated levels of TGF-P, in conjunction with down-regulation of TNF-a receptors, account for the suboptimal macrophage response to virulent Mycobacterium avium (3,4,14). In addition, the low-virulent Mycobacterium avium strain 1983 induced high levels of TNF-a that stimulated production of reactive oxygen intermediates leading to growth restriction mediated by hydrogen peroxide in the infected macrophages, whereas high-virulence strain ATCC 25291 induced low levels of TNFa and thus inhibited superoxide production by the infected macrophages (48,49). Due to a significantly higher TNF-a synthesis, alveolar macrophages were shown to inhibit the intracellular growth of Mycobacterium tuberculosis more effectively than blood monocytes (29).…”

Effector molecules of the host defence mechanism against Mycobacterium avium complex: the evidence showing that reactive oxygen intermediates, reactive nitrogen intermediates, and free fatty acids each alone are not decisive in expression of macrophage antimicrobial activity against the parasites

“…Second, the L-arginine-dependent cytotoxic pathway has been demonstrated to participate in macrophage antimycobacterial mechanisms, particularly in murine macrophages [8,9,15,16]. Reactive nitrogen intermediates (RNI) are reported to be the principal effectors of murine macrophages in antimicrobial functions against M. tuberculosis [9,[16][17][18].…”