Protection against progressive leishmaniasis by IFN-beta.
Type I IFNs (IFN-alphabeta) exert potent antiviral and immunoregulatory activities during viral infections, but their role in bacterial or protozoan infections is poorly understood. In this study, we demonstrate that the application of low, but not of high doses of IFN-beta protects 60 or 100% of BALB/c mice from progressive cutaneous and fatal visceral disease after infection with a high (10(6)) or low (10(4)) number of Leishmania major parasites, respectively. IFN-beta treatment of BALB/c mice restored the NK cell cytotoxic activity, increased the lymphocyte proliferation, and augmented the production of IFN-gamma and IL-12 in the draining lymph node. Low, but not high doses of IFN-beta caused enhanced tyrosine phosphorylation of STAT1 and STAT4, suppressed the levels of suppressor of cytokine signaling-1, and up-regulated the expression of inducible NO synthase in vivo. The IFN-beta-induced increase of IFN-gamma production was dependent on STAT4. Protection by IFN-beta strictly required the presence of inducible NO synthase. In the absence of STAT4 or IL-12, IFN-beta led to an amelioration of the cutaneous and visceral disease, but was unable to prevent its progression. These results identify IFN-beta as a novel cytokine with a strong, dose-dependent protective effect against progressive cutaneous leishmaniasis that results from IL-12- and STAT4-dependent as well as -independent events.
Mattner
Jochen
J
Institute of Clinical Microbiology, Immunology and Hygiene, University of Erlangen-Nuremberg, Erlangen, Germany.
Wandersee-Steinhäuser
Alexandra
A
Pahl
Andreas
A
Röllinghoff
Martin
M
Majeau
Gerard R
GR
Hochman
Paula S
PS
Bogdan
Christian
C
D000818:Animals; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D016899:Interferon-beta / Q000008:administration & dosage / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology; D007896:Leishmaniasis / Q000188:drug therapy* / Q000517:prevention & control; D016773:Leishmaniasis, Cutaneous / Q000517:prevention & control; D007898:Leishmaniasis, Visceral / Q000517:prevention & control; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D050797:STAT4 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism
D004268:DNA-Binding Proteins; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D015534:Trans-Activators; D018664:Interleukin-12; D016899:Interferon-beta; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse