Modulation of allergic inflammation in mice deficient in TNF receptors.
Tumor necrosis factor-alpha (TNF) is implicated as an important proinflammatory cytokine in asthma. We evaluated mice deficient in TNF receptor 1 (TNFR1) and TNFR2 [TNFR(-/-) mice] in a murine model of allergic inflammation and found that TNFR(-/-) mice had comparable or accentuated responses compared with wild-type [TNFR(+/+)] mice. The responses were consistent among multiple end points. Airway responsiveness after methacholine challenge and bronchoalveolar lavage (BAL) fluid leukocyte and eosinophil numbers in TNFR(-/-) mice were equivalent or greater than those observed in TNFR(+/+) mice. Likewise, serum and BAL fluid IgE; lung interleukin (IL)-2, IL-4, and IL-5 levels; and lung histological lesion scores were comparable or greater in TNFR(-/-) mice compared with those in TNFR(+/+) mice. TNFR(+/+) mice chronically treated with anti-murine TNF antibody had BAL fluid leukocyte numbers and lung lesion scores comparable to control antibody-treated mice. These results suggest that, by itself, TNF does not have a critical proinflammatory role in the development of allergic inflammation in this mouse model and that the production of other cytokines associated with allergic disease may compensate for the loss of TNF bioactivity in the TNFR(-/-) mouse.
Rudmann
D G
DG
Departments of Pathology and Immunology, Genentech, Incorporated, South San Francisco 94080, California, USA. daniel.g.rudmann@am.pnu.com
Moore
M W
MW
Tepper
J S
JS
Aldrich
M C
MC
Pfeiffer
J W
JW
Hogenesch
H
H
Tumas
D B
DB
D000336:Aerosols; D000818:Animals; D001249:Asthma / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D004195:Disease Models, Animal; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007371:Interferon-gamma / Q000032:analysis; D007376:Interleukin-2 / Q000032:analysis; D015847:Interleukin-4 / Q000032:analysis; D015848:Interleukin-5 / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D011014:Pneumonia / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics* / Q000276:immunology*; D012130:Respiratory Hypersensitivity / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D000336:Aerosols; D007074:Immunoglobulin G; D007376:Interleukin-2; D015848:Interleukin-5; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma; D010047:Ovalbumin