Mast cells play a key role in the development of late airway hyperresponsiveness through TNF-α in a murine model of asthma

We have investigated the role of TNF-α in mast cell-mediated late airway hyperresponsiveness (AHR) using mast cell-deficient WBB6F1-W/W^v (W/W^v) mice in a murine model of asthma, which exhibits a biphasic increase in AHR. TNF-α levels in the airway and magnitude of late AHR in response to airway allergen challenge were severely impaired in W/W^v mice compared to their littermates. In addition to TNF-α, cytosolic phospholipase A₂ (cPLA₂) phosphorylation and enzymatic activity in the lungs were also impaired in W/W^v mice. Either anti-TNF-α antibody or an inhibitor of cPLA₂ abolished late AHR in congeneic +/+ mice. Intratracheal administration of TNF-α resulted in increases in late AHR, cPLA₂ phosphorylation, cPLA₂ activity, and phosphorylation of mitogen-activated protein kinases. Mast cell replacement restored airway TNF-α level, cPLA₂ phosphorylation and enzymatic activity in the lungs as well as late AHR in W/W^v mice. These data indicate that mast cells play a key role in the development of late AHR through liberation of TNF-α.