Contribution of tumour necrosis factor-alpha (TNF-alpha) in host defence mechanism against Cryptococcus neoformans.
We investigated the role of TNF-alpha in the host defence mechanism against infection with a virulent strain of Cryptococcus neoformans. Administration of exogenous recombinant human TNF-alpha significantly prolonged the survival time of mice infected by intratracheal instillation of the organism. Surprisingly, neutralizing MoAb to murine TNF-alpha did not shorten their survival time, a finding inconsistent with previous results. To investigate the cause of this inconsistency, we examined the production of TNF-alpha in the lungs of infected mice. During the course of cryptococcosis, there was little or no generation of TNF-alpha mRNA in the lung. This might be partly due to a direct inhibitory action of the fungal microorganism of TNF-alpha production by macrophages. In vitro production of TNF-alpha by murine interferon-gamma (IFN-gamma)- and lipopolysaccharide (LPS)-stimulated macrophages was strongly inhibited by co-culturing with the whole yeast cells. In contrast, administration of recombinant murine IL-12 markedly induced TNF-alpha production and the neutralizing anti-TNF-alpha MoAb strongly blocked IL-12-induced protection of mice against cryptococcal infection. These results indicate that endogenously synthesized TNF-alpha has the potential to contribute to the elimination of C. neoformans and partly mediates the protective effect of IL-12.
Kawakami
K
K
First Department of Internal Medicine, Faculty of Medicine, University of the Ryukyus, Okinawa, Japan.
Qifeng
X
X
Tohyama
M
M
Qureshi
M H
MH
Saito
A
A
D000818:Animals; D000908:Antibodies, Fungal / Q000276:immunology; D001667:Binding, Competitive / Q000276:immunology; D003453:Cryptococcosis / Q000175:diagnosis / Q000276:immunology*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D008070:Lipopolysaccharides / Q000276:immunology; D008168:Lung / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D011379:Prognosis; D012333:RNA, Messenger / Q000032:analysis; D011994:Recombinant Proteins / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*
D000908:Antibodies, Fungal; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma