title: Blockade of endogenous TNF-alpha exacerbates primary and secondary pulmonary histoplasmosis by differential mechanisms.
abstract: We investigated the mechanisms by which endogenous TNF-alpha modulates host defenses during experimental primary and secondary pulmonary infection with Histoplasma capsulatum (Hc). Neutralization of TNF-alpha in vivo resulted in increased CFU and 100% mortality in naive and immune mice challenged with Hc intranasally. Levels of IFN-gamma and granulocyte macrophage-CSF were elevated in TNF-alpha-neutralized naive mice, whereas IL-4, -6, -10 and TGF-beta did not differ from controls. In contrast, in secondary histoplasmosis, significant elevations of IL-4 and -10 were observed in TNF-alpha-depleted mice. Alveolar macrophages (Mphi) did not exert fungistatic activity against Hc after exposure to recombinant murine TNF-alpha, recombinant murine IFN-gamma, or both. The increase in susceptibility to primary Hc infection was associated with diminished production of reactive nitrogen intermediates by alveolar Mphi from TNF-alpha-depleted mice, whereas production of nitric oxide during secondary histoplasmosis was similar in both groups. Upon secondary challenge, TNF-alpha-depleted mice were rescued by concomitant neutralization of IL-4 and IL-10, but not either cytokine alone. Thus, TNF-alpha is critical for controlling primary and secondary infection with Hc, and the mechanisms that lead mice to succumb to primary or secondary infection when endogenous TNF-alpha is blocked are different.
authors.affiliation: Division of Infectious Diseases, University of Cincinnati College of Medicine, OH 45267, USA.
authors.forename: R
authors.initials: R
authors.lastname: Allendoerfer
authors.forename: G S
authors.initials: GS
authors.lastname: Deepe
mesh_terms: D000818:Animals; D004198:Disease Susceptibility / Q000276:immunology; D005434:Flow Cytometry; D006660:Histoplasmosis / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology; D015847:Interleukin-4 / Q000276:immunology; D008172:Lung Diseases, Fungal / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D009584:Nitrogen / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015847:Interleukin-4; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D009584:Nitrogen