Antifungal type 1 responses are upregulated in IL-10-deficient mice

Microbes Infect. 1999 Dec;1(14):1169-80. doi: 10.1016/s1286-4579(99)00245-2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aspergillus fumigatus
  • CD4 Antigens / metabolism
  • Candida albicans
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Guanidines / pharmacology
  • Immunity, Cellular
  • Immunity, Innate
  • Inflammation
  • Interferon-gamma / metabolism
  • Interleukin-10 / genetics
  • Interleukin-10 / metabolism
  • Interleukin-10 / physiology*
  • Interleukin-12 / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mycoses / immunology*
  • Mycoses / microbiology
  • Mycoses / pathology
  • Nitric Oxide / antagonists & inhibitors
  • Nitric Oxide / metabolism
  • Nitric Oxide Synthase / antagonists & inhibitors
  • Polymerase Chain Reaction
  • RNA, Messenger / analysis
  • Th1 Cells / immunology
  • Th1 Cells / metabolism*
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • CD4 Antigens
  • Guanidines
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Interleukin-12
  • Nitric Oxide
  • Interferon-gamma
  • Nitric Oxide Synthase
  • pimagedine