CD40-MEDIATED SIGNAL-TRANSDUCTION IN HUMAN AIRWAY SMOOTH-MUSCLE

CD40 is a member of the TNF receptor family that was initially describ ed on the surface of B cells. Recently, CD40 has also been described o n mesenchymal cells, such as endothelial cells and fibroblasts, where engagement by its ligand CD40 ligand can lead to up-regulation of cost imulatory and cell adhesion molecules, as well as secretion of proinfl ammatory cytokines. Since airway inflammation potentially involves cel l-cell interactions of T cells and eosinophils (which express CD40 lig and) with airway smooth muscle (ASM) cells, we postulated that ASM may express CD40 and that engagement of ASM CD40 may modulate smooth musc le cell function. We demonstrate that CD40 is expressed on cultured hu man ASM and that expression can be increased by treatment with TNF-alp ha or IFN-gamma. Cross-linking CD40 on ASM resulted in enhanced IL-6 s ecretion and an increase in intracellular calcium concentrations, whic h were dependent an calcium influx, We show that CD40-mediated signali ng events include protein tyrosine phosphorylation and activation of N F-kappa B, Pretreatment of ASM with the tyrosine kinase inhibitors gen istein or herbimycin inhibited the rapid mobilization of calcium induc ed via CD40, suggesting that calcium mobilization was coupled to activ ation of protein tyrosine kinases, In addition, inhibition of calcium influx inhibited both CD40-mediated NF-kappa B activation and enhancem ent of IL-6 secretion, These results delineate a potentially important CD40-mediated signal-transduction pathway in ASM, involving protein t yrosine kinase-dependent calcium mobilization, NF-kappa B activation, and IL-6 production. Together, these results suggest a mechanism where by T cell/smooth muscle cell interactions may potentiate airway inflam mation.