title: Histamine metabolism and transport are deranged in human keratinocytes in oral lichen planus.
abstract: BACKGROUND
  Recent reports have indicated that nonimmune cells can produce low concentrations of histamine. This observation, together with the discovery of the high-affinity histamine H4receptor (H4R), has added additional layers of complexity to our understanding of histamine signalling. Human oral keratinocytes (HOKs) possess a uniform H4R pattern, which is deranged in oral lichen planus (OLP).
  
  
  OBJECTIVE
  To investigate histamine metabolism and transport in HOKs of healthy controls and patients with OLP.
  
  
  METHODS
  Tissue sections and cultured primary HOKs were studied using immunostaining, quantitative real-time polymerase chain reaction and confocal microscopy. Histamine levels were analysed using high-performance liquid chromatography.
  
  
  RESULTS
  l-histidine decarboxylase (HDC) and organic cation transporter (OCT)3 were increased in mRNA and protein levels in patients with OLP compared with controls. In contrast, histamine N-methyltransferase (HNMT) immunoreactivity was decreased in OLP. OCT1/OCT2 and diamine oxidase were not detectable in either tissue sections or in HOKs. Immunolocalization of HDC and OCT3 in HOKs revealed moderate-to-high expression within cytoplasm and cell boundaries. Stimulation with lipopolysaccharide (LPS) or interferon-γ upregulated HDC-gene transcript in HOKs, whereas this was downregulated with high histamine concentration and tumour necrosis factor-α. LPS induced a dose-dependent release of low histamine in HOKs, while high histamine concentration downregulated epithelial adhesion proteins.
  
  
  CONCLUSIONS
  HOKs are histamine-producing cells. They release histamine via OCT3 channels in concentrations too low to activate the classical low-affinity H1R and H2R, but high enough to stimulate the high-affinity H4R in autocrine and paracrine modes. The substantially deranged histamine metabolism and transport in OLP could, in part, contribute to the disease pathogenesis.
authors.affiliation: Department of Medicine, University of Helsinki, Helsinki, Finland.|Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Salem
authors.affiliation: Department of Anatomy, University of Helsinki, Helsinki, Finland.
authors.forename: S
authors.initials: S
authors.lastname: Rozov
authors.affiliation: Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Al-Samadi
authors.affiliation: Department of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: V
authors.initials: V
authors.lastname: Stegajev
authors.affiliation: Department of Medicine, University of Helsinki, Helsinki, Finland.|Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland.
authors.forename: D
authors.initials: D
authors.lastname: Listyarifah
authors.affiliation: Department of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: V-P
authors.initials: VP
authors.lastname: Kouri
authors.affiliation: Department of Medicine, University of Helsinki, Helsinki, Finland.
authors.forename: X
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Medicine, University of Helsinki, Helsinki, Finland.|Department of Rheumatology, Internal Medicine and Rehabilitation, University of Helsinki, Helsinki, Finland.|Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: D
authors.initials: D
authors.lastname: Nordström
authors.affiliation: Helsinki University Central Hospital, Helsinki, Finland.|Department of Pathology and Oral Pathology, University of Helsinki, Helsinki, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Hagström
authors.affiliation: Department of Medicine, University of Helsinki, Helsinki, Finland.|Department of Rheumatology, Internal Medicine and Rehabilitation, University of Helsinki, Helsinki, Finland.
authors.forename: K K
authors.initials: KK
authors.lastname: Eklund
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006631:Amine Oxidase (Copper-Containing) / Q000378:metabolism; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D006632:Histamine / Q000378:metabolism*; D006637:Histamine N-Methyltransferase / Q000378:metabolism; D006640:Histidine Decarboxylase / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D015603:Keratinocytes / Q000378:metabolism*; D017676:Lichen Planus, Oral / Q000209:etiology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008875:Middle Aged; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation / Q000502:physiology; D055815:Young Adult; D000099254:Organic Cation Transporter 3
chemical_list: D006631:Amine Oxidase (Copper-Containing); D006632:Histamine; D006637:Histamine N-Methyltransferase; D006640:Histidine Decarboxylase; D007371:Interferon-gamma; D008070:Lipopolysaccharides; D027701:Organic Cation Transport Proteins; D012333:RNA, Messenger; D000099254:Organic Cation Transporter 3