Substance P Activates Coincident NF-AT- and NF-κB-Dependent Adhesion Molecule Gene Expression in Microvascular Endothelial Cells Through Intracellular Calcium Mobilization

作者：Kimberly L. Quinlan, Shubhada M. Naik, Georgetta Cannon, Cheryl A. L. Armstrong, Nigel W. Bunnett, John C. Ansel, S. Wright Caughman · 发表于：The Journal of Immunology · 年份：1999 · DOI：10.4049/jimmunol.163.10.5656 · 被引用次数：91 · 研究领域：Neuropeptides and Animal Physiology、Signaling Pathways in Disease、Cell Adhesion Molecules Research

Abstract Upon stimulation, cutaneous sensory nerves release neuropeptides such as substance P (SP), which modulate responses in the skin by activating a number of target cells via neurokinin receptors. We have demonstrated that SP preferentially binds to the NK-1R on human dermal microvascular cells, resulting in increased intracellular Ca2+ and induction of ICAM-1 and VCAM-1 expression. In the current studies, we identify specific elements in the regulatory regions of ICAM-1 and VCAM-1 genes as necessary and sufficient for SP-dependent transcriptional activation. SP treatment of human dermal microvascular endothelial cells leads to coincident activation and binding of the transcription factor NF-AT to the −191/−170 region of the ICAM-1 gene (a region bound by activated p65/p65 homodimers in response to TNF-α), and NF-κB (p65/p50) to tandem NF-κB binding sites at −76/−52 of the VCAM-1 gene. The SP-elicited intracellular Ca2+ signal was required for activation and subsequent binding of both NF-AT and NF-κB. The transacting factor induction by SP was specific, since a selective NK-1R antagonist blocked SP activation and subsequent NF-AT and NF-κB activation and binding. These data demonstrate coincident activation of NF-AT and NF-κB via SP-induced intracellular Ca2+ mobilization and indicate a crucial role for neuropeptides in modulating localized cutaneous inflammatory responses.