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Am. J. Respir. Crit. Care Med., Volume 164, Number 12, December 2001, 2229-2238

Tumor Necrosis Factor-alpha Negatively Regulates Airway Hyperresponsiveness through gamma delta T Cells

ARIHIKO KANEHIRO, MICHAEL LAHN, MIKA J. MÄKELÄ, AZZEDDINE DAKHAMA, MASAKI FUJITA, ANTHONY JOETHAM, ROBERT J. MASON, WILLI BORN, and ERWIN W. GELFAND

Departments of Pediatrics, Immunology, and Medicine, National Jewish Medical and Research Center, Denver, Colorado

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. gamma delta T cells have been shown to be activated by TNF-alpha and to negatively regulate AHR. Depletion of gamma delta 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 gamma delta T cells.




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