title: Pituitary Adenylate Cyclase-Activating Polypeptide Is Upregulated in Murine Skin Inflammation and Mediates Transient Receptor Potential Vanilloid-1-Induced Neurogenic Edema.
abstract: Although pituitary adenylate cyclase-activating polypeptide (PACAP) was described as a key vasoregulator in human skin, little is known about its expression in mouse skin. As it is important to investigate PACAP signaling in translational mouse dermatitis models, we determined its presence, regulation, and role in neurogenic and non-neurogenic cutaneous inflammatory mechanisms. The mRNA of PACAP and its specific receptor PAC1 was detected with real-time PCR in several skin regions at comparable levels. PACAP-38-immunoreactivity measured with radioimmunoassay was similar in plantar and dorsal paw skin and the ear but significantly smaller in the back skin. PACAP and PAC1 mRNA, as well as PACAP-38 and PAC1 protein expression, significantly increased in the plantar skin after intraplantar administration of capsaicin (50 μl, 100 μg ml(-1)), an agonist of the transient receptor potential vanilloid 1 (TRPV1) receptor, evoking chiefly neurogenic inflammation without inflammatory cell accumulation. Intraplantar complete Freund's adjuvant (CFA; 50 μl, 1 mg ml(-1)) also increased PACAP/PAC1 mRNA but not the PACAP peptide. Capsaicin-induced neurogenic paw edema, but not CFA-evoked non-neurogenic swelling, was significantly smaller in PACAP-deficient mice throughout a 24-hour period. To our knowledge, we provide previously unreported evidence for PACAP and PAC1 expression upregulation during skin inflammation of different mechanisms and for its pro-inflammatory function in neurogenic edema formation.
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs, Hungary; János Szentágothai Research Center, University of Pécs, Pécs, Hungary; PharmInVivo Ltd., Pécs, Hungary; MTA NAP B Pain Research Group University of Pécs, School of Medicine, Pécs, Hungary. Electronic address: zsuzsanna.helyes@aok.pte.hu.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Helyes
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs, Hungary; János Szentágothai Research Center, University of Pécs, Pécs, Hungary; MTA NAP B Pain Research Group University of Pécs, School of Medicine, Pécs, Hungary.
authors.forename: Jozsef
authors.initials: J
authors.lastname: Kun
authors.affiliation: DE-MTA Lendület Cellular Physiology Research Group, Departments of Physiology and Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Nora
authors.initials: N
authors.lastname: Dobrosi
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs, Hungary.
authors.forename: Katalin
authors.initials: K
authors.lastname: Sándor
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.
authors.forename: Jozsef
authors.initials: J
authors.lastname: Németh
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs, Hungary.
authors.forename: Aniko
authors.initials: A
authors.lastname: Perkecz
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs, Hungary; János Szentágothai Research Center, University of Pécs, Pécs, Hungary; PharmInVivo Ltd., Pécs, Hungary.
authors.forename: Erika
authors.initials: E
authors.lastname: Pintér
authors.affiliation: János Szentágothai Research Center, University of Pécs, Pécs, Hungary; Department of Experimental Zoology and Neurobiology, Faculty of Sciences, University of Pecs, Pecs, Hungary.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Szabadfi
authors.affiliation: Department of Anatomy, MTA-PTE PACAP Lendület Research Group, Faculty of Medicine, University of Pécs, Pécs, Hungary.
authors.forename: Balazs
authors.initials: B
authors.lastname: Gaszner
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs, Hungary; János Szentágothai Research Center, University of Pécs, Pécs, Hungary.
authors.forename: Valeria
authors.initials: V
authors.lastname: Tékus
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs, Hungary; PharmInVivo Ltd., Pécs, Hungary.
authors.forename: Janos
authors.initials: J
authors.lastname: Szolcsányi
authors.affiliation: Department of Dermatology, Charles Clinic and UCD Charles Institute for Translational Dermatology, University College Dublin, Dublin, Ireland.
authors.forename: Martin
authors.initials: M
authors.lastname: Steinhoff
authors.affiliation: Laboratory of Molecular Neuropharmacology & iPS Cell-based Research Project on Brain Neuropharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan; United Graduate School of Child Development, Osaka University, Suita, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hashimoto
authors.affiliation: Department of Anatomy, MTA-PTE PACAP Lendület Research Group, Faculty of Medicine, University of Pécs, Pécs, Hungary.
authors.forename: Dora
authors.initials: D
authors.lastname: Reglődi
authors.affiliation: DE-MTA Lendület Cellular Physiology Research Group, Departments of Physiology and Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
authors.forename: Tamas
authors.initials: T
authors.lastname: Bíró
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D003872:Dermatitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020078:Neurogenic Inflammation / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D011863:Radioimmunoassay; D011897:Random Allocation; D018709:Statistics, Nonparametric; D050916:TRPV Cation Channels / Q000494:pharmacology*; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D012333:RNA, Messenger; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D002211:Capsaicin