Substance P activates coincident NF-AT- and NF-kappa B-dependent adhesion molecule gene expression in microvascular endothelial cells through intracellular calcium mobilization

J Immunol. 1999 Nov 15;163(10):5656-65.

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

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 5' Untranslated Regions / genetics
  • Calcium Signaling / physiology*
  • Cell Adhesion Molecules / genetics*
  • Cell Membrane / metabolism
  • Cells, Cultured
  • Cyclosporine / pharmacology
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology*
  • Dimerization
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / metabolism*
  • Endothelium, Vascular / physiology
  • Gene Expression Regulation*
  • Humans
  • Intercellular Adhesion Molecule-1 / biosynthesis
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / metabolism
  • Intracellular Fluid / metabolism*
  • NF-kappa B / metabolism
  • NF-kappa B / physiology*
  • NF-kappa B p50 Subunit
  • NFATC Transcription Factors
  • Nuclear Proteins*
  • Proto-Oncogene Proteins c-rel / metabolism
  • Response Elements / drug effects
  • Sequence Deletion
  • Substance P / physiology*
  • Transcription Factor AP-1 / metabolism
  • Transcription Factor RelA
  • Transcription Factors / metabolism
  • Transcription Factors / physiology*
  • Tumor Necrosis Factor-alpha / physiology
  • Vascular Cell Adhesion Molecule-1 / biosynthesis

Substances

  • 5' Untranslated Regions
  • Cell Adhesion Molecules
  • DNA-Binding Proteins
  • NF-kappa B
  • NF-kappa B p50 Subunit
  • NFATC Transcription Factors
  • Nuclear Proteins
  • Proto-Oncogene Proteins c-rel
  • Transcription Factor AP-1
  • Transcription Factor RelA
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1
  • Intercellular Adhesion Molecule-1
  • Substance P
  • Cyclosporine