title: Indomethacin inhibits eosinophil migration to prostaglandin D2 : therapeutic potential of CRTH2 desensitization for eosinophilic pustular folliculitis.
abstract: Indomethacin is a cyclo-oxygenase inhibitor, and shows therapeutic potential for various eosinophilic skin diseases, particularly eosinophilic pustular folliculitis. One of the unique characteristics of indomethacin is that, unlike other non-steroidal anti-inflammatory drugs, it is a potent agonist of chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2), a receptor for prostaglandin D2 (PGD2 ). This study investigated the pharmacological actions of indomethacin on eosinophil migration to clarify the actual mechanisms underlying the therapeutic effects of indomethacin on eosinophilic pustular folliculitis. Eosinophils exhibited chemokinetic and chemotactic responses to both PGD2 and indomethacin through CRTH2 receptors. Pre-treatment of eosinophils with indomethacin greatly inhibited eosinophil migration to PGD2 and, to a much lesser extent, to eotaxin (CCL11); these effects could be mediated by homologous and heterologous desensitization of eosinophil CRTH2 and CCR3, respectively, by agonistic effects of indomethacin on CRTH2. Indomethacin also cancelled a priming effect of Δ(12) -PGJ2 , a plasma metabolite of PGD2 , on eosinophil chemotaxis to eotaxin. Indomethacin down-modulated cell surface expression of both CRTH2 and CCR3. Hair follicle epithelium and epidermal keratinocytes around eosinophilic pustules together with the eccrine apparatus of palmoplantar lesions of eosinophilic pustular folliculitis were immunohistochemically positive for lipocalin-type PGD synthase. Indomethacin may exert therapeutic effects against eosinophilic skin diseases in which PGD2 -CRTH2 signals play major roles by reducing eosinophil responses to PGD2 .
authors.affiliation: Department of Dermatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Kataoka
authors.forename: Takahiro
authors.initials: T
authors.lastname: Satoh
authors.forename: Aiko
authors.initials: A
authors.lastname: Hirai
authors.forename: Kazumi
authors.initials: K
authors.lastname: Saeki
authors.forename: Hiroo
authors.initials: H
authors.lastname: Yokozeki
mesh_terms: D002465:Cell Movement / Q000187:drug effects; D054413:Chemokine CCL11 / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003888:Desensitization, Immunologic; D015536:Down-Regulation / Q000187:drug effects; D004802:Eosinophilia / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D004804:Eosinophils / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D005499:Folliculitis / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology*; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D054834:Lipocalins / Q000378:metabolism; D015230:Prostaglandin D2 / Q000276:immunology*; D054397:Receptors, CCR3 / Q000378:metabolism; D011971:Receptors, Immunologic / Q000819:agonists* / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000819:agonists* / Q000378:metabolism; D012872:Skin Diseases, Vesiculobullous / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism
chemical_list: C515456:CCL11 protein, human; C515350:CCR3 protein, human; D054413:Chemokine CCL11; D016861:Cyclooxygenase Inhibitors; D054834:Lipocalins; D054397:Receptors, CCR3; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C499810:delta(12)-prostaglandin J(2); D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D015230:Prostaglandin D2; D007213:Indomethacin; C036293:prostaglandin D2 receptor
keywords: CCR3; Lipocalin-type prostaglandin D synthase; chemoattractant receptor-homologous molecule expressed on T helper type 2 cells; desensitization; eotaxin