IFN-beta impairs superoxide-dependent parasite killing in human macrophages: evidence for a deleterious role of SOD1 in cutaneous leishmaniasis.
Type I IFNs (IFN-alpha/beta) have only recently gained considerable attention as immunomodulators in nonviral infectious diseases. IFN-beta has been shown to protect, in a NO-dependent manner, against murine Old World leishmaniasis caused by Leishmania major, but data in New World leishmaniasis are lacking. We found that IFN-beta dose-dependently increases parasite burden in Leishmania amazonensis- as well as Leishmania braziliensis-infected human macrophages, independent of endogenous or exogenous NO. However, IFN-beta significantly reduced superoxide release in Leishmania-infected as well as uninfected human macrophages. This decrease in superoxide production was paralleled by a significant IFN-beta-mediated increase in superoxide dismutase 1 (SOD1) protein levels. Additionally, IFN-beta inhibition of leishmanicidal activity was mimicked by SOD1 and antagonized by either pharmacological or small interfering RNA-mediated inhibition of SOD1. Finally, pronounced SOD1 expression in situ was demonstrated in biopsies from New World cutaneous leishmaniasis patients. These findings reveal a hitherto unknown IFN-beta/SOD1 axis in Leishmania infection and suggest that inhibition of SOD-associated pathways could serve as strategy in the treatment of L. amazonensis as well as L. braziliensis infection, major human pathogens.
Khouri
Ricardo
R
Laboratory of Immunoregulation and Microbiology, Centro de Pesquisa Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador- Bahia, Brazi.
Bafica
André
A
Silva
Maria da Purificação Pereira
Mda P
Noronha
Almerio
A
Kolb
Jean-Pierre
JP
Wietzerbin
Juana
J
Barral
Aldina
A
Barral-Netto
Manoel
M
Van Weyenbergh
Johan
J
D002478:Cells, Cultured; D006801:Humans; D007150:Immunohistochemistry; D016899:Interferon-beta / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000469:parasitology; D009569:Nitric Oxide / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013482:Superoxide Dismutase / Q000276:immunology* / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D013481:Superoxides / Q000276:immunology* / Q000378:metabolism
C000606290:SOD1 protein, human; D013481:Superoxides; D009569:Nitric Oxide; D016899:Interferon-beta; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1