Antibody-mediated depletion of tumor necrosis factor-alpha impairs pulmonary host defenses to Legionella pneumophila.
Tumor necrosis factor-alpha (TNF-alpha) has been shown to stimulate the resistance of alveolar macrophages and neutrophils to Legionella pneumophila in vitro. To determine whether endogenous TNF-alpha is necessary for host defense against legionellosis in vivo, anti-TNF-alpha IgG or control IgG was administered to rats exposed to aerosolized L. pneumophila. Treatment with anti-TNF-alpha neutralized >90% of the intrapulmonary TNF-alpha response to infection, resulting in persistent pneumonitis and failure to clear L. pneumophila from the lungs. Depletion of TNF-alpha limited the recruitment of mononuclear cells to the lungs and resulted in a progressive increase in the proportion of alveolar macrophages that were infected; neutrophil recruitment and phagocytosis were not impaired. Both systemic and intrapulmonary IFN-gamma levels were significantly higher in rats depleted of TNF-alpha. These observations indicate that TNF-alpha is required for the prompt resolution of pneumonic legionellosis and point to a direct role for TNF-alpha in the activation of phagocytes.
Skerrett
S J
SJ
Department of Veterans Affairs Puget Sound Health Care System, and Department of Medicine, University of Washington School of Medicine, Seattle 98108, USA.
Bagby
G J
GJ
Schmidt
R A
RA
Nelson
S
S
D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage / Q000032:analysis / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000276:immunology; D007371:Interferon-gamma / Q000032:analysis / Q000378:metabolism; D007877:Legionnaires' Disease / Q000276:immunology*; D008168:Lung / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D008262:Macrophage Activation / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology / Q000382:microbiology; D008297:Male; D009079:Mucociliary Clearance / Q000276:immunology; D018375:Neutrophil Activation / Q000276:immunology; D009504:Neutrophils / Q000276:immunology / Q000502:physiology; D010587:Phagocytosis / Q000276:immunology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013047:Specific Pathogen-Free Organisms; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000276:immunology
D019138:Antibodies, Blocking; D007074:Immunoglobulin G; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma