Interferon-gamma reduces the capacity of human alveolar macrophages to inhibit growth of Cryptococcus neoformans in vitro.

Abstract

Cytokine stimulation of mouse and rat macrophages has previously been shown to enhance their capacity to phagocytose and inhibit the growth of Cryptococcus neoformans. To extend these observations to primary human macrophages, we investigated the anticryptococcal activity of human alveolar macrophages stimulated with interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), or macrophage-colony stimulating factor (M-CSF). Neither TNF-alpha nor M-CSF had any effect on fungal growth inhibition compared with unstimulated macrophages. Alveolar macrophages stimulated with IFN-gamma demonstrated reduced fungistasis for C. neoformans compared with controls (49% +/- 15% versus 75% +/- 12%; mean % growth inhibition +/- SD, P < 0.001). Confocal laser scanning microscopy was used to assess binding and phagocytosis of yeast. No difference was observed between unstimulated macrophages and macrophages stimulated with any of the cytokines tested. These data suggest that the cytokine regulation of anticryptococcal macrophage functions in humans differs from the rat and mouse. Conclusions drawn from these models may not necessarily be applicable to human cryptococcosis. In particular, the effects of IFN-gamma on the interaction of human alveolar macrophages with C. neoformans was not predicted based on the mouse and rat macrophage responses.

Cytokine Signaling Regulates the Outcome of Intracellular Macrophage Parasitism byCryptococcus neoformans

“…First, it is intriguing that IFN-␥ suppresses the cryptococcal IPR in J774 cells far more effectively than that in human primary macrophages. This observation is in agreement with the data in previous reports demonstrating a reduction in the inhibition of cryptococcal growth in human alveolar and monocyte-derived macrophages after IFN-␥ treatment (30,44). Such findings may indicate differences in IFN-␥-related regulation of anticryptococcal functions between mouse and human macrophages.…”

“…IFN-␥ has clearly been demonstrated to have a protective role in mouse model systems of cryptococcosis (5,24) and to increase fungicidal activity of murine macrophages (19). However, among human cells, IFN-␥ treatment reduces the capacity of human alveolar macrophages (44) and human monocyte-derived macrophages (30) to inhibit cryptococcal growth, a finding that is supported by our data. Although IFN-␥ levels at the site of infection have been negatively correlated with cryptococcal CFU (47) and IFN-␥ therapy has proved to be successful for one patient (41), these in vitro data suggest that IFN-␥ treatment may not always be an appropriate therapeutic approach.…”

Cryptococcal Interactions with the Host Immune System

“…It is therefore likely that a shift to a Th2 environment results in activation changes in phagocytic effector cells and hence to a change in the composition of phagolysosomes. However, IFN-␥ treatment increases the intracellular growth of C. neoformans in human macrophages (104,157), suggesting that aspects of this response may be host species specific.…”

“…IFN-␥ levels at the site of infection correlate with fungal burden (169), and administration of IFN-␥ has successfully improved the outcome of systemic cryptococcosis in mouse model systems (23,116) and in one human patient (144). However, although IFN-␥ seems to have a protective role in mice (7,68) and to increase fungicidal activity of murine macrophages (50), the same treatment reduces anticryptococcal activity in human macrophages (104,157), suggesting that this line of treatment may be less advantageous for human patients.…”

Identification of App1 as a regulator of phagocytosis and virulence of Cryptococcus neoformans

“…Introductionmacrophages (AMs) represent one of the cell types that inhibit and kill C. neoformans (12,13). During the initiation process, T cells are activated, and through the release of macrophage-activating cytokines they promote the formation of granulomas, resulting in the destruction of the intracellular fungus or containment in a latent state (dormancy) (11).…”