Interleukin‐4 and interleukin‐10 inhibit nitric oxide‐dependent macrophage killing of Candida albicans

Abstract

Mouse peritoneal and splenic macrophages treated with interferon-gamma (IFN-gamma) and infected with the yeast Candida albicans expressed high fungicidal activity in vitro that correlated with increased nitrite concentrations in culture supernatants. Both effects were reduced by an inhibitor of nitric oxide (NO) synthesis which, in vivo, impaired the animals' ability to mount a footpad reaction and clear the fungus from infected organs. Because T helper type-2 (Th2) cytokines in candidiasis are known to limit the expression of protective Th1 functions, we tested the effect of interleukin (IL)-4 and IL-10 on candidacidal activity and NO production of IFN-gamma-activated macrophages. Fungal killing and NO secretion were inhibited, in a dose-dependent manner, by the two cytokines either separately or in combination. Impaired candidacidal activity was also demonstrable in the presence of monoiodoacetic acid, an inhibitor of phagocytosis. These data demonstrate that NO is involved in macrophage killing of C. albicans and support the notion that regulation of Th1 effector function by IL-4 and IL-10 might involve modulation of NO synthesis.

Macrophage expression of class II major histocompatibility complex gene products in Paracoccidioides brasiliensis-infected mice.

“…Production of NO by macrophages obtained from animals infected with strains PB265 and Pb18 reached maximum levels on the 15th and 60th days, respectively, after infection. This mediator is the major microbicidal agent of macrophages, capable of controlling many infections caused by intracellular parasites such as L. major, 29 Mycobacterium bovis, 30 Toxoplasma gondii, 31 Schistosoma mansoni, 32 Trypanosoma cruzi, 33 and Candida albicans, 34 among others, and even P. brasiliensis, which is destroyed in vitro in the presence of NO donors. 35 In the present study, the NO levels observed at the beginning of infection must be associated with the ability of NO to promote immunosuppression of the lymphoproliferative response.…”

Nitric oxide mediates the microbicidal activity of eosinophils

“…Nitric oxide (NO) or nitrogen-derived metabolites have been identified as major effector molecules involved in the macrophage microbicidal activity against most intracellular pathogens, including L. major (Liew & Millott 1990), Toxoplasma gondii (Adams et al 1990), T. musculi (Vincendeau & Dalouede 1991), T. cruzi (Gazzinelli et al 1992), P. berghei (Mellouk et al 1991), Mycobacterium leprae (Adams et al 1991), M. avium (Denis 1991), Candida albicans (Cenci et al 1993) and the virus Ectromelia, vaccinia and herpes simplex-1 (Gunasegaran et al 1993). Recently, it was demonstrated that the microbicidal activity of neutrophils against C. albicans is also mediated by NO (Fierro et al 1996).…”

“…An important protective role for reactive nitrogen intermediates has been established in macrophage killing of intracellular protozoa (Liew & Millott 1990, Adams et al 1990, Vincendeau & Dalouede 1991, Gazzinelli et al 1992, bacteria (Adams et al 1991, Denis 1991, fungus (Cenci et al 1993) and virus (Gunasegaran et al 1993). A similar role has also been demonstrated in neutrophil killing of C. albicans (Fierro et al 1996) and Staphilococcus aureus (Malawista et al 1992).…”

Herbal supplement formula of Elephantopus scaber and Sauropus androgynus promotes IL-2 cytokine production of CD4+T cells in pregnant mice with typhoid fever

“…IL-4 cytokine can inhibit the secretion of IL-12 and IFN-γ [34,35,36]. IL-4 also inhibits phagocytosis and intracellular killing [37,38], and suppresses inflammatory cytokine production [39]. In the E. scaber and S. androgynus treatment, the number of IL-4 cytokine and B220 + decrease.…”