title: Antifungal type 1 responses are upregulated in IL-10-deficient mice.
abstract: C57BL/6 mice are highly resistant to infections caused by Candida albicans and Aspergillus fumigatus. To elucidate the role of IL-10 produced by C57BL/6 mice during these infections, parameters of infection and immunity to it were evaluated in IL-10-deficient and wild-type mice with disseminated or gastrointestinal candidiasis or invasive pulmonary aspergillosis. Unlike parasitic protozoan infection, C. albicans or A. fumigatus infection did not induce significant acute toxicity in IL-10-deficient mice, who, instead, showed reduced fungal burden and fungal-associated inflammatory responses. The increased resistance to infections as compared to wild-type mice was associated with upregulation of innate and acquired antifungal Th1 responses, such as a dramatically higher production of IL-12, nitric oxide (NO) and TNF-alpha as well as IFN-gamma by CD4+ T cells. Pharmacological inhibition of NO production greatly reduced resistance to gastrointestinal candidiasis, thus pointing to the importance of IL-10-dependent NO regulation at mucosal sites in fungal infections. These results are reminiscent of those obtained in genetically susceptible mice, in which IL-10 administration increased, and IL-10 neutralization decreased, susceptibility to C. albicans and A. fumigatus infections. Collectively, these observations indicate that the absence of IL-10 augments innate and acquired antifungal immunity by upregulating type 1 cytokine responses. The resulting protective Th1 responses lead to a prompt reduction of fungal growth, thus preventing tissue destruction and lethal levels of proinflammatory cytokines.
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Del Sero
authors.forename: A
authors.initials: A
authors.lastname: Mencacci
authors.forename: E
authors.initials: E
authors.lastname: Cenci
authors.forename: C F
authors.initials: CF
authors.lastname: d'Ostiani
authors.forename: C
authors.initials: C
authors.lastname: Montagnoli
authors.forename: A
authors.initials: A
authors.lastname: Bacci
authors.forename: P
authors.initials: P
authors.lastname: Mosci
authors.forename: M
authors.initials: M
authors.lastname: Kopf
authors.forename: L
authors.initials: L
authors.lastname: Romani
mesh_terms: D000818:Animals; D001232:Aspergillus fumigatus; D015704:CD4 Antigens / Q000378:metabolism; D002176:Candida albicans; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006146:Guanidines / Q000494:pharmacology; D007111:Immunity, Cellular; D007113:Immunity, Innate; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018664:Interleukin-12 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009181:Mycoses / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D015704:CD4 Antigens; D006146:Guanidines; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; C004479:pimagedine