title: cis-Urocanic acid stimulates primary human keratinocytes independently of serotonin or platelet-activating factor receptors.
abstract: Urocanic acid (UCA) is a major epidermal chromophore that undergoes trans to cis isomerization after ultraviolet radiation (UVR). cis-UCA suppresses cell-mediated immunity. Recent studies suggest that cis-UCA binds to serotonin (5-hydroxytryptamine) 2A (5-HT(2A)) receptor and that antagonists of 5-HT(2A) and the platelet-activating factor (PAF) receptor can block cis-UCA-induced immune suppression in mice. Here, we examined the involvement of 5-HT(2A) and PAF receptors in the ability of cis-UCA to stimulate immunomodulatory mediator production in primary human keratinocytes. Using real-time reverse transcription-PCR (RT-PCR), PAF but not 5-HT(2A) receptor mRNA was constitutively expressed in primary human keratinocytes. Treatment with cis-UCA increased prostaglandin E(2) (PGE(2)), tumor necrosis factor-alpha (TNF-alpha), and IL-6 secretion, whereas 5-HT only stimulated IL-6 production. Pretreatment with a 5-HT receptor antagonist partially inhibited IL-6 increase by 5-HT, but did not inhibit mediator production by cis-UCA. Similarly, a PAF receptor antagonist did not inhibit cis-UCA-induced increase in PGE(2). Intracellular calcium mobilization studies using a human epithelial cell line stably transfected with PAF receptor also showed little evidence that cis-UCA stimulated PAF receptor and it did not bind to this receptor. Thus, cis-UCA stimulates mediator production by a pathway that is independent of these receptors in human keratinocytes, and these cells may not be the major target for cis-UCA-induced immune suppression.
authors.affiliation: King's College London, St John's Institute of Dermatology, King's College London School of Medicine, London, UK.
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Kaneko
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Travers
authors.forename: Mary S
authors.initials: MS
authors.lastname: Matsui
authors.forename: Antony R
authors.initials: AR
authors.lastname: Young
authors.forename: Mary
authors.initials: M
authors.lastname: Norval
authors.forename: Susan L
authors.initials: SL
authors.lastname: Walker
mesh_terms: D002478:Cells, Cultured; D015232:Dinoprostone / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000502:physiology*; D015850:Interleukin-6 / Q000378:metabolism; D007536:Isomerism; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D008711:Metergoline / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014560:Urocanic Acid / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D010980:Platelet Membrane Glycoproteins; D012333:RNA, Messenger; D044402:Receptor, Serotonin, 5-HT2A; D043562:Receptors, G-Protein-Coupled; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists; D014409:Tumor Necrosis Factor-alpha; C039351:platelet activating factor receptor; D008711:Metergoline; D014560:Urocanic Acid; D015232:Dinoprostone