Neutralization of IL-10 up-regulates nitric oxide production and protects susceptible mice from challenge with Candida albicans.
In contrast to several inbred strains of mice that develop Th1-associated anticandidal protection, DBA/2 mice are highly susceptible to systemic infection with Candida albicans cells of the attenuated variant PCA-2, and fatal outcome is observed in concurrence with sustained CD4+ cell production in vitro of IL-4 and IL-10. These Th2 cytokines were previously shown to inhibit nitric oxide (NO) production and yeast killing by activated macrophage cultures. We now show that macrophages from DBA/2 mice, either intact or infected with PCA-2, have lower capacity than resistant strains to synthesize NO in response to IFN-gamma. However, when treated with anti-IL-10 Abs at the time of infection, DBA/2 mice survived challenge and displayed increased production of NO in vitro after IFN-gamma activation. Cure was associated with the onset of footpad responses and durable protection, and higher frequencies of IFN-gamma-secreting cells were found in splenic CD4+ lymphocytes that expressed lower levels of IL-4 and IL-10 mRNA. Therefore, in DBA/2 mice, IL-10 contributes significantly to the selection of a Th2 response and lethality after PCA-2 challenge. An IL-10-induced defect in the activation and/or expansion of IFN-gamma-producing Th1 cells, IL-10 suppression of yeast killing, and the relative inability of DBA/2 macrophages to produce adequate levels of candidacidal NO may all contribute to the abnormal susceptibility of these mice to candidiasis.
Romani
L
L
Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Italy.
Puccetti
P
P
Mencacci
A
A
Cenci
E
E
Spaccapelo
R
R
Tonnetti
L
L
Grohmann
U
U
Bistoni
F
F
D000818:Animals; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002177:Candidiasis / Q000503:physiopathology*; D003602:Cytotoxicity, Immunologic; D017931:DNA Primers / Q000737:chemistry; D005260:Female; D015870:Gene Expression; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000502:physiology*; D015847:Interleukin-4 / Q000235:genetics; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics
D017931:DNA Primers; D012333:RNA, Messenger; D016753:Interleukin-10; D015847:Interleukin-4; D009569:Nitric Oxide; D007371:Interferon-gamma