Tumor necrosis factor-α negatively regulates airway hyperresponsiveness through γδ T cells

Arihiko Kanehiro, Michael Lahn, Mika J. Mäkelä, Azzeddine Dakhama, Masaki Fujita, Anthony Joetham, Robert J. Mason, Willi Born, Erwin W. Gelfand

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)


Tumor necrosis factor (TNF)-α is a potent cytokine with immunomodulatory, proroinflammatory, and pathobiologic activities. Although TNF-α is thought to play a role in mediating airway inflammation and airway hyperresponsiveness (AHR), its function is not well defined. TNF-α - deficient mice and mice expressing TNF-α in their lungs because of a TNF-α transgene placed under the control of the surfactant protein (SP)-C promoter (SP-C/TNF-α - 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-α - deficient mice, AHR was significantly increased over that in controls. In contrast, the transgenic mice failed to develop AHR. In addition, sensitized/challenged TNF-α - 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-α - 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. γδ T cells have been shown to be activated by TNF-α and to negatively regulate AHR. Depletion of γδ T cells in the TNF-α - transgenic mice in the present study increased AHR, whereas depletion of these cells had no significant effect in TNF-α - deficient mice. These data indicate that TNF-α can negatively modulate airway responsiveness, controlling airway function in allergen-induced AHR through the activation of γδ T cells.

Original languageEnglish
Pages (from-to)2229-2238
Number of pages10
JournalAmerican Journal of Respiratory and Critical Care Medicine
Issue number12
Publication statusPublished - Dec 15 2002


  • Airway hyperresponsiveness
  • Inflammation
  • TNF-α
  • γδ T cells

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine


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