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*
Pulmonary and Critical Care Division, Department of Medicine, Hospital of University of Pennsylvania, Philadelphia, PA 19104;
Immunex Corporation, Seattle, WA 98101; and
The Wistar Institute, Philadelphia, PA 19104
CD40 is a member of the TNF receptor family that was initially
described on the surface of B cells. Recently, CD40 has also been
described on mesenchymal cells, such as endothelial cells and
fibroblasts, where engagement by its ligand CD40 ligand can lead to
up-regulation of costimulatory and cell adhesion molecules, as well as
secretion of proinflammatory cytokines. Since airway inflammation
potentially involves cell-cell interactions of T cells and eosinophils
(which express CD40 ligand) with airway smooth muscle (ASM) cells, we
postulated that ASM may express CD40 and that engagement of ASM CD40
may modulate smooth muscle cell function. We demonstrate that CD40 is
expressed on cultured human ASM and that expression can be increased by
treatment with TNF-
or IFN-
. Cross-linking CD40 on ASM resulted
in enhanced IL-6 secretion and an increase in intracellular calcium
concentrations, which were dependent on calcium influx. We show that
CD40-mediated signaling events include protein tyrosine phosphorylation
and activation of NF-
B. Pretreatment of ASM with the tyrosine kinase
inhibitors genistein or herbimycin inhibited the rapid mobilization of
calcium induced via CD40, suggesting that calcium mobilization was
coupled to activation of protein tyrosine kinases. In addition,
inhibition of calcium influx inhibited both CD40-mediated NF-B
activation and enhancement of IL-6 secretion. These results delineate a
potentially important CD40-mediated signal-transduction pathway in ASM,
involving protein tyrosine kinase-dependent calcium mobilization,
NF-B activation, and IL-6 production. Together, these results
suggest a mechanism whereby T cell/smooth muscle cell interactions may
potentiate airway inflammation.
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