title: Stimulation of the histamine 4 receptor upregulates thymic stromal lymphopoietin (TSLP) in human and murine keratinocytes.
abstract: The cytokine thymic stromal lymphopoietin (TSLP) is involved in the development and the progression of allergic diseases. It is mainly released by epithelial cells at barriers such as skin and gut in response to danger signals. Overexpression of TSLP in keratinocytes (KC) can provoke the development of a type 2 inflammatory response. Additionally, TSLP directly acts on sensory neurons and thereby triggers itch. Since histamine is also increased in lesions of inflammatory skin diseases, the aim of this study was to investigate possible effects of histamine as well as different histamine receptor subtype agonists and antagonists on TSLP production in KC. We therefore stimulated human KC with histamine in the presence or absence of the known TSLP-inductor poly I:C and measured TSLP production at protein as well as mRNA level. Histamine alone did not induce TSLP production in human KC, but pre-incubation with histamine prior to challenge with poly I:C resulted in a significant increase of TSLP production compared to stimulation with poly I:C alone. Experiments with different histamine receptor agonists (H1R: 2-pyridylethylamine; H2R: amthamine; H2R/H4R: 4-methylhistamine (4MH)) revealed a dominant role for the H4R receptor, as 4-MH in combination with poly I:C displayed a significant increase of TSLP secretion, while the other agonists did not show any effect. The increase in TSLP production by 4MH was blocked with the H4R antagonist JNJ7777120. This effect was reproducible also in the murine KC cell line MSC. Taken together, our study indicates a new role for the H4 receptor in the regulation of TSLP in keratinocytes. Therefore, blocking of the H4R receptor in allergic diseases might be promising to alleviate inflammation and pruritus via TSLP.
authors: Division of Immunodermatology and Allergy Research, Department of Dermatology and Allergy, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany. Electronic address: schaper.katrin@mh-Hannover.de.
authors: Katrin
authors: K
authors: Schaper
authors: Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Foundation, Buenteweg 17, Hannover, Germany.
authors: Kristine
authors: K
authors: Rossbach
authors: Division of Immunodermatology and Allergy Research, Department of Dermatology and Allergy, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
authors: Brigitta
authors: B
authors: Köther
authors: Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University, Universitaetsstr. 1, 40225 Duesseldorf, Germany.
authors: Holger
authors: H
authors: Stark
authors: Department of Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Foundation, Buenteweg 17, Hannover, Germany.
authors: Manfred
authors: M
authors: Kietzmann
authors: Division of Immunodermatology and Allergy Research, Department of Dermatology and Allergy, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
authors: Thomas
authors: T
authors: Werfel
authors: Division of Immunodermatology and Allergy Research, Department of Dermatology and Allergy, Hannover Medical School, Carl-Neuberg-Straße 1, 30625 Hannover, Germany.
authors: Ralf
authors: R
authors: Gutzmer
mesh_terms: D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000187:drug effects* / Q000378:metabolism; D057809:HEK293 Cells; D006632:Histamine / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D008761:Methylhistamines / Q000494:pharmacology; D051379:Mice; D011070:Poly I-C / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011968:Receptors, Histamine / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D016207:Cytokines; D008761:Methylhistamines; D011725:Pyridines; D012333:RNA, Messenger; D011968:Receptors, Histamine; C025566:4-methylhistamine; D006632:Histamine; C006183:2-(2-aminoethyl)pyridine; D011070:Poly I-C; D000094632:Thymic Stromal Lymphopoietin
keywords: Histamine; Histamine 4 receptor; Keratinocytes; TSLP