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-alpha), and NF-kappa B (p65/p50) to tandem NF-kappa B 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-kappa B. The transacting factor induction by SP was specific, since a selective NK-1R antagonist blocked SP activation and subsequent NF-AT and NF-kappa B activation and binding. These data demonstrate coincident activation of NF-AT and NF-kappa B via SP-induced intracellular Ca2+ mobilization and indicate a crucial role for neuropeptides in modulating localized cutaneous inflammatory responses.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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5' Untranslated Regions / genetics
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Calcium Signaling / physiology*
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Cell Adhesion Molecules / genetics*
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Cell Membrane / metabolism
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Cells, Cultured
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Cyclosporine / pharmacology
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / metabolism
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DNA-Binding Proteins / physiology*
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Dimerization
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Endothelium, Vascular / cytology
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Endothelium, Vascular / metabolism*
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Endothelium, Vascular / physiology
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Gene Expression Regulation*
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Humans
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Intercellular Adhesion Molecule-1 / biosynthesis
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Intercellular Adhesion Molecule-1 / genetics
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Intercellular Adhesion Molecule-1 / metabolism
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Intracellular Fluid / metabolism*
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NF-kappa B / metabolism
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NF-kappa B / physiology*
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NF-kappa B p50 Subunit
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NFATC Transcription Factors
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Nuclear Proteins*
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Proto-Oncogene Proteins c-rel / metabolism
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Response Elements / drug effects
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Sequence Deletion
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Substance P / physiology*
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Transcription Factor AP-1 / metabolism
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Transcription Factor RelA
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Transcription Factors / metabolism
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Transcription Factors / physiology*
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Tumor Necrosis Factor-alpha / physiology
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Vascular Cell Adhesion Molecule-1 / biosynthesis
Substances
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5' Untranslated Regions
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Cell Adhesion Molecules
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DNA-Binding Proteins
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NF-kappa B
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NF-kappa B p50 Subunit
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NFATC Transcription Factors
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Nuclear Proteins
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Proto-Oncogene Proteins c-rel
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Transcription Factor AP-1
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Transcription Factor RelA
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Transcription Factors
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Tumor Necrosis Factor-alpha
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Vascular Cell Adhesion Molecule-1
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Intercellular Adhesion Molecule-1
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Substance P
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Cyclosporine