Tumor necrosis factor-alpha negatively regulates airway hyperresponsiveness through gamma-delta T cells.
Tumor necrosis factor (TNF)-alpha is a potent cytokine with immunomodulatory, proinflammatory, and pathobiologic activities. Although TNF-alpha is thought to play a role in mediating airway inflammation and airway hyperresponsiveness (AHR), its function is not well defined. TNF-alpha-deficient mice and mice expressing TNF-alpha in their lungs because of a TNF-alpha transgene placed under the control of the surfactant protein (SP)-C promoter (SP-C/TNF-alpha-transgenic mice) were sensitized to ovalbumin (OVA) and subsequently challenged with OVA via the airways; airway function in response to inhaled methacholine was monitored. In the TNF-alpha-deficient mice, AHR was significantly increased over that in controls. In contrast, the transgenic mice failed to develop AHR. In addition, sensitized/ challenged TNF-alpha-deficient mice had significantly increased numbers of eosinophils and higher levels of interleukin (IL)-5 and IL-10 in their bronchoalveolar lavage fluid than were found for control mice. However, in SP-C/TNF-alpha-transgenic mice, both the numbers of eosinophils and levels of IL-5 and IL-10 were significantly lower than in sensitized/challenged transgene-negative mice. gammadelta T cells have been shown to be activated by TNF-alpha and to negatively regulate AHR. Depletion of gammadelta T cells in the TNF-alpha-transgenic mice in the present study increased AHR, whereas depletion of these cells had no significant effect in TNF-alpha-deficient mice. These data indicate that TNF-alpha can negatively modulate airway responsiveness, controlling airway function in allergen-induced AHR through the activation of gammadelta T cells.
Kanehiro
A
A
Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206, USA.
Lahn
M
M
Mäkelä
M J
MJ
Dakhama
A
A
Fujita
M
M
Joetham
A
A
Mason
R J
RJ
Born
W
W
Gelfand
E W
EW
D000485:Allergens / Q000276:immunology; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000378:metabolism / Q000503:physiopathology*; D001985:Bronchial Provocation Tests; D016207:Cytokines / Q000378:metabolism; D007073:Immunoglobulin E / Q000032:analysis; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D016210:Methacholine Chloride; D051379:Mice; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D011510:Proteolipids / Q000235:genetics; D011663:Pulmonary Surfactants / Q000235:genetics; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis*; D013601:T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*
D000485:Allergens; D016207:Cytokines; D011510:Proteolipids; D011663:Pulmonary Surfactants; D016692:Receptors, Antigen, T-Cell, gamma-delta; D014409:Tumor Necrosis Factor-alpha; D016210:Methacholine Chloride; D007073:Immunoglobulin E; D010047:Ovalbumin