Differential role of IL-18 and IL-12 in the host defense against disseminated Candida albicans infection.
IFN-gamma plays a crucial role in the defense against infection with Candida albicans. Since IL-18 and IL-12 are strong stimuli of IFN-gamma production, we investigated whether endogenous IL-18 and IL-12 are involved in the host defense during disseminated candidiasis. IL-18 knockout (IL-18-/-) mice, but not IL-12-/- mice, displayed an increased mortality due to C. albicans infection, accompanied by a decreased clearance of the yeasts from the kidneys late during the course of infection. Histopathology of the organs, combined with phagocyte recruitment experiments, showed a decreased influx of monocytes at the sites of Candida infection, mainly in the IL-18-/- mice. Whereas production of the chemokine KC was decreased in both IL-18-/- and IL-12-/- mice, MIP-2 production was deficient only in IL-18-/- animals, which may explain the differences in phagocyte recruitment. In addition, although IFN-gamma production capacity, as a parameter of the Th1-protective immunity, was reduced by 65 to 80% in the IL-12-/- mice, this defect was even more pronounced in the IL-18-/- mice (85 to 95% down-modulation). In conclusion, the anticandidal effects of endogenous IL-18 are mediated late during the infection by assuring a proper IFN-gamma response and promoting the infiltration of the site of infection by monocytes.
Netea
Mihai G
MG
Department of Medicine, University Medical Center St. Radboud, Nijmegen, Nijmegen, The Netherlands.
Vonk
Alieke G
AG
van den Hoven
Mabel
M
Verschueren
Ineke
I
Joosten
Leo A
LA
van Krieken
Johan H
JH
van den Berg
Wim B
WB
Van der Meer
Jos W M
JW
Kullberg
Bart Jan
BJ
D000818:Animals; D002177:Candidiasis / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000502:physiology*; D020382:Interleukin-18 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D010587:Phagocytosis
D016207:Cytokines; D020382:Interleukin-18; D018664:Interleukin-12; D007371:Interferon-gamma