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Candidacidal mechanisms of peritoneal macrophages activated with lymphokines or gamma-interferon
1Department of Medicine, Santa Clara Valley Medical Center, San Jose, CA 95128.
Abstract:
The mechanisms by which resident peritoneal macrophages, activated in vitro by lymphokines (LK) or recombinant gamma-interferon (IFN), kill Candida parapsilosis or C. albicans were studied. Resident non-activated peritoneal macrophages killed C. parapsilosis (55.5% SD 6.8%), but not C. albicans. This killing was completely inhibited by superoxide dismutase (SOD), partially by dimethyl sulphoxide (DMSO), but not by catalase or azide. Killing correlated with a brisk lucigenin-dependent chemiluminescence (CL) response by macrophages interacting with C. parapsilosis. No enhanced luminol-dependent CL response was observed in this system. This suggests that C. parapsilosis is killed by resident macrophages via a mechanism dependent on the presence of superoxide anion. By contrast, killing of C. parapsilosis by activated macrophages (49.0% SD 5.9%) was not inhibited by SOD or DMSO, suggesting the induction of a non-oxidative candidacidal mechanism. C. albicans was killed only by macrophages activated with IFN (52.0% SD 3.7%) or LK (55.7% SD 2.8%). Inhibition of killing by SOD was greater in IFN- than in LK-activated macrophages. Conversely, killing by LK-, but not IFN-, activated macrophages was significantly inhibited by catalase, DMSO or azide. The killing by LK-activated macrophages, and its inhibition by scavengers, correlated with the luminol-dependent CL response. The non-killing resident macrophages interacting with C. albicans made lucigenin-dependent CL responses similar to those of activated macrophages. The mechanisms enabling killing of C. albicans induced by activation appear to be different for LK and IFN, and appear to depend upon the myeloperoxidase systems and superoxide respectively.
Insights
Resident macrophages kill Candida parapsilosis using superoxide anion, while activated macrophages use non-oxidative mechanisms. Killing Candida albicans requires activation, with distinct pathways for lymphokines and gamma-interferon.
Area of Science:
- Immunology
- Microbiology
- Cell Biology
Background:
- Peritoneal macrophages play a crucial role in innate immunity against fungal infections.
- Understanding macrophage-mediated killing mechanisms is vital for developing antifungal strategies.
- Candida species, particularly C. parapsilosis and C. albicans, are common opportunistic fungal pathogens.
Purpose of the Study:
- To elucidate the distinct mechanisms employed by resident and activated peritoneal macrophages in killing Candida parapsilosis and Candida albicans.
- To investigate the roles of oxidative and non-oxidative pathways in macrophage-mediated fungal killing.
- To differentiate the candidacidal mechanisms induced by lymphokines (LK) and recombinant gamma-interferon (IFN).
Main Methods:
- Peritoneal macrophages (resident and activated with LK or IFN) were incubated with C. parapsilosis and C. albicans.
- Macrophage killing activity was assessed, and the involvement of reactive oxygen species (ROS) was evaluated using inhibitors like superoxide dismutase (SOD), catalase, dimethyl sulphoxide (DMSO), and azide.
- Chemiluminescence (CL) responses (lucigenin-dependent and luminol-dependent) were measured to correlate with specific killing mechanisms.
Main Results:
- Resident macrophages killed C. parapsilosis via a superoxide anion-dependent mechanism, evidenced by SOD inhibition and lucigenin-dependent CL.
- Activated macrophages exhibited non-oxidative killing of C. parapsilosis, unaffected by SOD or DMSO.
- Only activated macrophages killed C. albicans, with IFN-activated cells showing SOD-sensitive killing and LK-activated cells demonstrating myeloperoxidase-dependent killing (inhibited by catalase, DMSO, azide) and luminol-dependent CL.
Conclusions:
- Resident macrophages primarily utilize superoxide for C. parapsilosis killing.
- Macrophage activation induces distinct candidacidal mechanisms against C. albicans, differing between LK and IFN stimuli.
- The findings highlight the complexity of macrophage-host-pathogen interactions and suggest differential therapeutic targets for Candida infections.