Substance P activates coincident NF-AT- and NF-kappa B-dependent adhesion molecule gene expression in microvascular endothelial cells through intracellular calcium mobilization.
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.
Quinlan
K L
KL
Department of Dermatology, Emory Skin Diseases Research Core Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
Naik
S M
SM
Cannon
G
G
Armstrong
C A
CA
Bunnett
N W
NW
Ansel
J C
JC
Caughman
S W
SW
D020121:5' Untranslated Regions / Q000235:genetics; D020013:Calcium Signaling / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D019281:Dimerization; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D007424:Intracellular Fluid / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D052002:NF-kappa B p50 Subunit; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism; D020218:Response Elements / Q000187:drug effects; D017384:Sequence Deletion; D013373:Substance P / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D051996:Transcription Factor RelA; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
D020121:5' Untranslated Regions; D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D020569:Proto-Oncogene Proteins c-rel; D018808:Transcription Factor AP-1; D051996:Transcription Factor RelA; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D013373:Substance P; D016572:Cyclosporine