Inhibitors of dipeptidyl peptidase IV and aminopeptidase N target major pathogenetic steps in acne initiation.
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.
Thielitz
Anja
A
Department of Dermatology and Venereology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany. anja.thielitz@medizin.uni-magdeburg.de
Reinhold
Dirk
D
Vetter
Robert
R
Bank
Ute
U
Helmuth
Martin
M
Hartig
Roland
R
Wrenger
Sabine
S
Wiswedel
Ingrid
I
Lendeckel
Uwe
U
Kähne
Thilo
T
Neubert
Klaus
K
Faust
Jürgen
J
Zouboulis
Christos C
CC
Ansorge
Siegfried
S
Gollnick
Harald
H
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
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