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Am J Physiol Lung Cell Mol Physiol 292: L430-L437, 2007. First published October 13, 2006; doi:10.1152/ajplung.00475.2005
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Tachykinin-1 receptor stimulates proinflammatory gene expression in lung epithelial cells through activation of NF-B via a G_q-dependent pathway

¹Section of Pulmonology, Department of Pediatrics, and ²Section of Pulmonary Diseases, Critical Care and Environmental Medicine, Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana

Submitted 9 November 2005 ; accepted in final form 9 October 2006

The respiratory tract is innervated by irritant-responsive sensory nerves, which, on stimulation, release tachykinin neuropeptides in the lung. Tachykinins modulate inflammatory responses to injury by binding to tachykinin (neurokinin) receptors present on various pulmonary cell types. In the present study, the activation of the proinflammatory transcription factor NF-B in lung epithelial cells was investigated as a mechanism by which tachykinins stimulate inflammatory processes. In A549 human lung epithelial cells transfected with the tachykinin-1 receptor (Tacr1), treatment with the Tacr1 ligand substance P (SP) resulted in NF-B activation, as judged by transcription of an NF-B-luciferase reporter gene and production of interleukin-8, a chemokine whose expression is upregulated by NF-B. SP caused a dose-dependent activation of NF-B that was inhibited by the selective Tacr1 antagonist RP67580. Tacr1 is a G protein-coupled receptor capable of activating both the G_q and G_s families of G proteins. Expression of inhibitory peptides and constitutively active G protein mutants revealed that G_q signaling was both necessary for Tacr1-induced NF-B activation and sufficient for NF-B activation in the absence of any other treatment. Treatment with pharmacological inhibitors to investigate events downstream of G_q revealed that Tacr1-induced NF-B activation proceeded through an intracellular signaling pathway that was dependent on phospholipase C, calcium, Ras, Raf-1, MEK, Erk, and proteasome function. These results identify intracellular signaling mechanisms that underlie the proinflammatory effects of tachykinins, which previously have been implicated in lung injury and disease.

substance P; A549; Erk; G protein-coupled receptor

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