title: Keratinocyte expression of calcitonin gene-related peptide β: implications for neuropathic and inflammatory pain mechanisms.
abstract: Calcitonin gene-related peptide (CGRP) is a vasodilatory peptide that has been detected at high levels in the skin, blood, and cerebrospinal fluid (CSF) under a variety of inflammatory and chronic pain conditions, presumably derived from peptidergic C and Aδ innervation. Herein, CGRP immunolabeling (IL) was detected in epidermal keratinocytes at levels that were especially high and widespread in the skin of humans from locations afflicted with postherpetic neuralgia (PHN) and complex region pain syndrome type 1 (CRPS), of monkeys infected with simian immunodeficiency virus, and of rats subjected to L5/L6 spinal nerve ligation, sciatic nerve chronic constriction, and subcutaneous injection of complete Freund's adjuvant. Increased CGRP-IL was also detected in epidermal keratinocytes of transgenic mice with keratin-14 promoter driven overexpression of noggin, an antagonist to BMP-4 signaling. Transcriptome microarray, quantitative Polymerase Chain Reaction (qPCR), and Western blot analyses using laser-captured mouse epidermis from transgenics, monolayer cultures of human and mouse keratinocytes, and multilayer human keratinocyte organotypic cultures, revealed that keratinocytes express predominantly the beta isoform of CGRP. Cutaneous peptidergic innervation has been shown to express predominantly the alpha isoform of CGRP. Keratinocytes also express the cognate CGRP receptor components, Calcitonin receptor-like receptor (CRLR), Receptor activity-modifying protein 1 (RAMP1), CGRP-receptor component protein (RCP) consistent with known observations that CGRP promotes several functional changes in keratinocytes, including proliferation and cytokine production. Our results indicate that keratinocyte-derived CGRPβ may modulate epidermal homeostasis through autocrine/paracrine signaling and may contribute to chronic pain under pathological conditions.
authors.affiliation: Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, NY, USA Department of Neurology, Albany Medical College, Albany, NY, USA Division of Human Anatomy, Department of Biomedical Sciences and Biotechnologies, University of Brescia, Brescia, Italy Department of Dermatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Department of Biology, Boston College, Chestnut Hill, MA, USA Rambam Medical Center, Faculty of Medicine, Israel Institute of Technology, Haifa, Israel Medical Oncology Branch, National Cancer Institute, Bethesda, MD, USA Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Center for Functional Genomics, SUNY Albany, Rensselaer, NY, USA In Vivo Pharmacology, Vertex Pharmaceuticals, San Diego, CA, USA Integrated Tissue Dynamics, LLC, Rensselaer, NY, USA.
authors.forename: Quanzhi
authors.initials: Q
authors.lastname: Hou
authors.forename: Travis
authors.initials: T
authors.lastname: Barr
authors.forename: Lucy
authors.initials: L
authors.lastname: Gee
authors.forename: Jeff
authors.initials: J
authors.lastname: Vickers
authors.forename: James
authors.initials: J
authors.lastname: Wymer
authors.forename: Elisa
authors.initials: E
authors.lastname: Borsani
authors.forename: Luigi
authors.initials: L
authors.lastname: Rodella
authors.forename: Spiro
authors.initials: S
authors.lastname: Getsios
authors.forename: Trisha
authors.initials: T
authors.lastname: Burdo
authors.forename: Elan
authors.initials: E
authors.lastname: Eisenberg
authors.forename: Udayan
authors.initials: U
authors.lastname: Guha
authors.forename: Robert
authors.initials: R
authors.lastname: Lavker
authors.forename: John
authors.initials: J
authors.lastname: Kessler
authors.forename: Sridar
authors.initials: S
authors.lastname: Chittur
authors.forename: Dennis
authors.initials: D
authors.lastname: Fiorino
authors.forename: Frank
authors.initials: F
authors.lastname: Rice
authors.forename: Phillip
authors.initials: P
authors.lastname: Albrecht
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D019898:Autocrine Communication / Q000235:genetics; D015740:Calcitonin Gene-Related Peptide / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D018836:Inflammation Mediators / Q000502:physiology*; D015603:Keratinocytes / Q000378:metabolism*; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009437:Neuralgia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019899:Paracrine Communication / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D055815:Young Adult
chemical_list: D018836:Inflammation Mediators; D015740:Calcitonin Gene-Related Peptide