title: Inhibitors of dipeptidyl peptidase IV and aminopeptidase N target major pathogenetic steps in acne initiation.
abstract: Acne is a chronic disease hallmarked by sebaceous hyperplasia, follicular hyperkeratosis, and inflammation. Parallel targeting of these factors is required to treat acne effectively. Inhibitors of dipeptidyl peptidase IV (DP IV) and aminopeptidase N (APN) show strong anti-inflammatory effects on immune cells and therapeutic efficacy in autoimmune disorders. Our investigation focused on the expression and functional relevance of these ectopeptidases in three cell types which exhibit an altered phenotype in early acne lesions. We showed for the first time expression of DP IV and APN on human sebocytes. In the SZ95 sebocyte cell line, the DP IV inhibitors Lys[Z(NO2)]-thiazolidide and Lys[Z(NO2)]-pyrrolidide and the APN inhibitors actinonin and bestatin suppressed proliferation, enhanced terminal differentiation, and slightly decreased total neutral lipid production. The anti-inflammatory and differentiation-restoring cytokine IL-1 receptor antagonist was significantly upregulated in SZ95 sebocytes and the HaCaT keratinocyte cell line in the presence of inhibitors. Furthermore, the inhibitors suppressed proliferation and IL-2 production of Propionibacterium acnes-stimulated T cells ex vivo and enhanced the expression of the immunosuppressive cytokine transforming growth factor-beta1. Our data provide first evidence for a functional role of DP IV and APN in the sebaceous gland apparatus and for their inhibitors, used alone or in combination, as completely new substances possibly affecting acne pathogenesis in a therapeutic manner.
authors.affiliation: Department of Dermatology and Venereology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany. anja.thielitz@medizin.uni-magdeburg.de
authors.forename: Anja
authors.initials: A
authors.lastname: Thielitz
authors.forename: Dirk
authors.initials: D
authors.lastname: Reinhold
authors.forename: Robert
authors.initials: R
authors.lastname: Vetter
authors.forename: Ute
authors.initials: U
authors.lastname: Bank
authors.forename: Martin
authors.initials: M
authors.lastname: Helmuth
authors.forename: Roland
authors.initials: R
authors.lastname: Hartig
authors.forename: Sabine
authors.initials: S
authors.lastname: Wrenger
authors.forename: Ingrid
authors.initials: I
authors.lastname: Wiswedel
authors.forename: Uwe
authors.initials: U
authors.lastname: Lendeckel
authors.forename: Thilo
authors.initials: T
authors.lastname: Kähne
authors.forename: Klaus
authors.initials: K
authors.lastname: Neubert
authors.forename: Jürgen
authors.initials: J
authors.lastname: Faust
authors.forename: Christos C
authors.initials: CC
authors.lastname: Zouboulis
authors.forename: Siegfried
authors.initials: S
authors.lastname: Ansorge
authors.forename: Harald
authors.initials: H
authors.lastname: Gollnick
mesh_terms: D000152:Acne Vulgaris / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D018826:CD13 Antigens / Q000037:antagonists & inhibitors / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018819:Dipeptidyl Peptidase 4 / Q000502:physiology*; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D012627:Sebaceous Glands / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology
chemical_list: D000900:Anti-Bacterial Agents; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D053590:Interleukin 1 Receptor Antagonist Protein; D018826:CD13 Antigens; D018819:Dipeptidyl Peptidase 4; D007930:Leucine; C012211:ubenimex; C010531:actinonin