Blockade of endogenous TNF-α exacerbates primary and secondary pulmonary histoplasmosis by differential mechanisms.

  • Allendoerfer R
  • Deepe G
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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.

Author-supplied keywords

  • Alveolar
  • Alveolar: immunology
  • Alveolar: metabolism
  • Animals
  • Disease Susceptibility
  • Disease Susceptibility: immunology
  • Flow Cytometry
  • Fungal
  • Fungal: immunology
  • Histoplasmosis
  • Histoplasmosis: immunology
  • Inbred C57BL
  • Interleukin-10
  • Interleukin-10: immunology
  • Interleukin-4
  • Interleukin-4: immunology
  • Lung Diseases
  • Macrophages
  • Male
  • Mice
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nitric Oxide Synthase: metabolism
  • Nitrogen
  • Nitrogen: metabolism
  • Th2 Cells
  • Th2 Cells: immunology
  • Tumor Necrosis Factor-alpha
  • Tumor Necrosis Factor-alpha: antagonists & inhibit
  • Tumor Necrosis Factor-alpha: immunology
  • Tumor Necrosis Factor-alpha: physiology

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