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-alpha in mast cell-mediated late airway hyperresponsiveness (AHR) using mast cell-deficient WBB6F1-W/W-nu (W/W-nu) mice in a murine model of asthma, which exhibits a biphasic increase in AHR. TNF-alpha, levels in the airway and magnitude of late AHR in response to airway allergen challenge were severely impaired in W/W-nu mice compared to their littermates. In addition to TNF-alpha, cytosolic phospholipase A(2) (cPLA(2)) phosphorylation and enzymatic activity in the lungs were also impaired in W/W-nu mice. Either anti-TNF-alpha antibody or an inhibitor of cPLA2 abolished late AHR in congeneic +/+ mice. Intratracheal administration of TNF-alpha, resulted in increases in late AHR, cPLA2 phosphorylation, cPLA2 activity, and phosphorylation of mitogen-activated protein kinases. Mast cell replacement restored airway TNF-alpha level, cPLA2 phosphorylation and enzymatic activity in the lungs as well as late AHR in W/W-nu mice. These data indicate that mast cells play a key role in the development of late AHR through liberation of TNF-alpha.