title: Histamine transport and metabolism are deranged in salivary glands in Sjogren's syndrome.
abstract: OBJECTIVE
  To study histamine transport and metabolism of salivary gland (SG) epithelial cells in healthy controls and SS patients.
  
  
  METHODS
  Enzymes and transporters involved in histamine metabolism were analysed in cultured human submandibular salivary gland (HSG) epithelial cells and tissue sections using quantitative real-time PCR and immunostaining. HSG cells were used to study [(3)H]histamine uptake [(±1-methyl-4-phenylpyridinium (MPP)] and efflux by liquid scintillation counting.
  
  
  RESULTS
  mRNA levels of l-histidine decarboxylase (HDC) and histamine-N-methyltransferase (HNMT) were similar in the control and SS glands, but diamine oxidase was not expressed at all. Organic cation transporter 3 (OCT3) in healthy SG was localized in the acinar and ductal cells, whereas OCT2 was restricted to the myoepithelial cells. Both transporters were significantly decreased in SS at mRNA and protein levels. OCT3-mRNA levels in HSG cells were significantly higher than those of the other studied transporters. Uptake of [(3)H]histamine was inhibited by MPP in a time-dependent manner, whereas [(3)H]histamine-preloaded HSG cells released it.
  
  
  CONCLUSIONS
  Ductal epithelial cells are non-professional histamine-producing cells able to release histamine via OCTs at the resting state up to ∼100 nM, enough to excite H3R/H4R(+) epithelial cells, but not H1R, which requires burst release from mast cells. At the stimulated phase, 50-60 μM histamine passes from the interstitial fluid through the acinar cells to saliva, whereas uptake by ductal cells leads to intracellular degradation by HNMT. OCT3/histamine/H4R-mediated cell maintenance and down-regulation of high histamine levels fail in SS SGs.
authors.affiliation: Department of Medicine, Institute of Clinical Medicine, Finland.
authors.forename: Vasily
authors.initials: V
authors.lastname: Stegaev
authors.forename: Anne T
authors.initials: AT
authors.lastname: Nies
authors.forename: Pauliina
authors.initials: P
authors.lastname: Porola
authors.forename: Diana
authors.initials: D
authors.lastname: Mieliauskaite
authors.forename: Francisca
authors.initials: F
authors.lastname: Sánchez-Jiménez
authors.forename: Jóse L
authors.initials: JL
authors.lastname: Urdiales
authors.forename: Tarvo
authors.initials: T
authors.lastname: Sillat
authors.forename: Hubert G
authors.initials: HG
authors.lastname: Schwelberger
authors.forename: Paul L
authors.initials: PL
authors.lastname: Chazot
authors.forename: Mwape
authors.initials: M
authors.lastname: Katebe
authors.forename: Zygmunt
authors.initials: Z
authors.lastname: Mackiewicz
authors.forename: Yrjö T
authors.initials: YT
authors.lastname: Konttinen
authors.forename: Dan C E
authors.initials: DC
authors.lastname: Nordström
mesh_terms: D001692:Biological Transport / Q000502:physiology*; D002478:Cells, Cultured; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism*; D006632:Histamine / Q000378:metabolism*; D006637:Histamine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006640:Histidine Decarboxylase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D012859:Sjogren's Syndrome / Q000378:metabolism*; D013363:Submandibular Gland / Q000378:metabolism*; D000099254:Organic Cation Transporter 3
chemical_list: D006632:Histamine; D006637:Histamine N-Methyltransferase; D006640:Histidine Decarboxylase; D027701:Organic Cation Transport Proteins; D000075102:Organic Cation Transporter 2; D000099254:Organic Cation Transporter 3; C491013:SLC22A2 protein, human
keywords: Sjögren’s syndrome; histamine; histamine receptor; organic cation transporters; salivary glands