A sub-inhibitory concentration of amphotericin B enhances candidastatic activity of interferon-gamma- and interleukin-13-treated murine peritoneal macrophages

Abstract

We studied the effects of interferon-gamma (IFN-gamma), a Th1 cytokine, and interleukin-13 (IL-13) or interleukin-4 (IL-4), Th2 cytokines, on the antifungal activity of resident murine peritoneal macrophages against Candida albicans 'in vitro'. IFN-gamma, IL-13 and IL-4 treatment enhanced the candidastatic functions of the macrophages. Reactive oxygen intermediates (ROIs) seem to be directly involved in the increase of anti-Candida activity in macrophages treated with Th1 or Th2 cytokines. Study of unopsonized C. albicans phagocytosis showed that IFN-gamma reduces the uptake process whereas the Th2 cytokines increase it. This difference is correlated to mannose receptor expression, which is decreased by IFN-gamma but increased by the Th2 cytokines. So, the effects on phagocytosis and candidastatic activity of IFN-gamma-treated macrophages are dissociated. In contrast, the phagocytic ability of macrophages pretreated 'in vitro' with IL-4 or IL-13 played a complementary role to the ROIs, in reduction of yeast proliferation by macrophages. In consequence, the macrophages treated with IL-13 and IL-4 develop a higher fungistatic activity than macrophages activated by IFN-gamma. Amphotericin B associated with IL-13 or IFN-gamma, but not with IL-4, enhanced the yeast growth inhibition activity of macrophages. The ROIs were involved in the additive effect of IFN-gamma with amphotericin B, whereas another mechanism was implicated in the increase of candidastatic activity of macrophages treated with IL-13 in association with amphotericin B.

IL-13 Attenuates Gastrointestinal Candidiasis in Normal and Immunodeficient RAG-2−/− Mice via Peroxisome Proliferator-Activated Receptor-γ Activation

“…Classically, protective immunity to C. albicans infection results from the development of Th1 responses (25). So, cytokines produced by Th1 cells, such as IFN-␥, activate phagocytic cells to a candidacidal state, increasing the secretion of effector molecules such as ROIs (10). Th2 cytokines, IL-4 and IL-13, were subsequently found to be more than simple inhibitors of macrophage activation, as they elicit a different activation program, termed macrophage alternative activation (23).…”

“…Alternatively activated macrophages express MR, arginase I, FIZZ-1, and Ym-1 (23). The role of these macrophages alternatively activated by IL-13 in C. albicans killing has been recently described (6,10). Indeed, we showed previously that in an unopsonized context, as found in immunocompromised hosts with no T or B cells, in vitro IL-13-treated macrophages express a high level of MR and hence attenuate C. albicans proliferation by increasing their ability to phagocytose the yeasts and to produce ROI but not NO (10).…”

“…The role of these macrophages alternatively activated by IL-13 in C. albicans killing has been recently described (6,10). Indeed, we showed previously that in an unopsonized context, as found in immunocompromised hosts with no T or B cells, in vitro IL-13-treated macrophages express a high level of MR and hence attenuate C. albicans proliferation by increasing their ability to phagocytose the yeasts and to produce ROI but not NO (10). Although Th2 cytokines are clearly responsible for in vitro macrophage alternative activation, few works show the in vivo involvement of these macrophages in infectious processes.…”

“…Binding or internalization of natural or synthetic ligands of MR may modulate macrophage functions, including respiratory burst (6) and synthesis of proinflammatory cytokines, such as IL-1␤, IL-6, and GM-CSF (7) to increase their microbicidal capacity. Previous studies have shown that MR expression can be positively modulated in vitro by many agents, in particular by 1,25-dihydroxyvitamin D3 (8), prostaglandin E 2 (9), IL-4, and IL-13 (10,11). Further support for a role of IL-13 in the control of the innate immune response came from the characterization of susceptibility to infection of animals that were deficient in IL-13.…”

Combination Treatment of Invasive Fungal Infections

“…Effective antifungal agents may act in collaboration with host effector cells at var- (29,30,213). Overall, various antifungals combined with immunomodulators against candidiasis have been shown to be generally more effective than monotherapy (30,38,112,149,232). Adjunctive immunotherapy using antibody-based therapies has been investigated for C. neoformans and A. fumigatus infections and generally shows enhanced activity with combination therapies (34,69,152,153,157,192,231).…”