title: Blunted epidermal L-tryptophan metabolism in vitiligo affects immune response and ROS scavenging by Fenton chemistry, part 1: Epidermal H2O2/ONOO(-)-mediated stress abrogates tryptophan hydroxylase and dopa decarboxylase activities, leading to low serotonin and melatonin levels.
abstract: Vitiligo is characterized by a progressive loss of inherited skin color. The cause of the disease is still unknown. To date, there is accumulating in vivo and in vitro evidence for massive oxidative stress via hydrogen peroxide (H(2)O(2)) and peroxynitrite (ONOO(-)) in the skin of affected individuals. Autoimmune etiology is the favored theory. Since depletion of the essential amino acid L-tryptophan (Trp) affects immune response mechanisms, we here looked at epidermal Trp metabolism via tryptophan hydroxylase (TPH) with its downstream cascade, including serotonin and melatonin. Our in situ immunofluorescence and Western blot data reveal significantly lower TPH1 expression in patients with vitiligo. Expression is also low in melanocytes and keratinocytes under in vitro conditions. Although in vivo Fourier transform-Raman spectroscopy proves the presence of 5-hydroxytryptophan, epidermal TPH activity is completely absent. Regulation of TPH via microphthalmia-associated transcription factor and L-type calcium channels is severely affected. Moreover, dopa decarboxylase (DDC) expression is significantly lower, in association with decreased serotonin and melatonin levels. Computer simulation supports H(2)O(2)/ONOO(-)-mediated oxidation/nitration of TPH1 and DDC, affecting, in turn, enzyme functionality. Taken together, our data point to depletion of epidermal Trp by Fenton chemistry and exclude melatonin as a relevant contributor to epidermal redox balance and immune response in vitiligo.
authors.affiliation: Institute for Pigmentary Disorders, E. M. Arndt University, Greifswald, Germany. k.schallreuter@bradford.ac.uk
authors.forename: Karin U
authors.initials: KU
authors.lastname: Schallreuter
authors.forename: Mohamed A E L
authors.initials: MA
authors.lastname: Salem
authors.forename: Nick C J
authors.initials: NC
authors.lastname: Gibbons
authors.forename: Aurora
authors.initials: A
authors.lastname: Martinez
authors.forename: Radomir
authors.initials: R
authors.lastname: Slominski
authors.forename: Jürgen
authors.initials: J
authors.lastname: Lüdemann
authors.forename: Hartmut
authors.initials: H
authors.lastname: Rokos
mesh_terms: D000328:Adult; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002478:Cells, Cultured; D004296:Dopa Decarboxylase / Q000378:metabolism*; D004817:Epidermis / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008550:Melatonin / Q000378:metabolism*; D008875:Middle Aged; D010084:Oxidation-Reduction; D030421:Peroxynitrous Acid / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D014364:Tryptophan / Q000737:chemistry / Q000378:metabolism*; D014365:Tryptophan Hydroxylase / Q000378:metabolism*; D014820:Vitiligo / Q000276:immunology / Q000378:metabolism*
chemical_list: D020746:Calcium Channels, L-Type; D017382:Reactive Oxygen Species; D030421:Peroxynitrous Acid; D012701:Serotonin; D014364:Tryptophan; D006861:Hydrogen Peroxide; D014365:Tryptophan Hydroxylase; D004296:Dopa Decarboxylase; D008550:Melatonin