TY - JOUR
T1 - Tumor necrosis factor-α negatively regulates airway hyperresponsiveness through γδ T cells
AU - Kanehiro, Arihiko
AU - Lahn, Michael
AU - Mäkelä, Mika J.
AU - Dakhama, Azzeddine
AU - Fujita, Masaki
AU - Joetham, Anthony
AU - Mason, Robert J.
AU - Born, Willi
AU - Gelfand, Erwin W.
PY - 2002/12/15
Y1 - 2002/12/15
N2 - 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.
AB - 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.
KW - Airway hyperresponsiveness
KW - Inflammation
KW - TNF-α
KW - γδ T cells
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U2 - 10.1164/ajrccm.164.12.2012059
DO - 10.1164/ajrccm.164.12.2012059
M3 - Article
C2 - 11751192
AN - SCOPUS:0037114202
VL - 164
SP - 2229
EP - 2238
JO - American Review of Respiratory Disease
JF - American Review of Respiratory Disease
SN - 1073-449X
IS - 12
ER -