[Frontiers in Bioscience 13, 2364-2375, January 1, 2008]

The ectopeptidases dipeptidyl peptidase IV (DP IV) and aminopeptidase N (APN) and their related enzymes as possible targets in the treatment of skin diseases

Anja Thielitz1, Siegfried Ansorge2, Ute Bank2, Michael Tager2, Sabine Wrenger3, Harald Gollnick1, Dirk Reinhold3

1 University Clinic of Dermatology and Venereology, Otto-von-Guericke University Magdeburg, Germany, 2 IMTM GmbH, Department Immunopharm, Magdeburg, Germany, 3Institute of Immunology, Otto-von-Guericke University Magdeburg, Germany

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Expression of DP IV and APN and their related enzymes in skin cells
4. Treatment of acne: Broad attack with ectopeptidase inhibitors
4.1. Pathogenesis of Acne
4.2. Inhibitor effects on three major pathogenetic factors of acne
4.2.1. Hyperseborrhea
4.2.1.1. SZ95 sebocytes
4.2.1.2. Syrian Hamster
4.2.2. Follicular Hyperkeratosis (HaCaT and Primary Keratinocytes)
4.2.3. Inflammation (P.acnes stimulated T cells)
5. Role of ectopeptidase inhibitors in the treatment of psoriasis
5.1. Pathogenesis of psoriasis
5.2. In vitro effects of ectopeptidase inhibitors
5.3. Inhibitor effects in the mouse tail model of psoriasis
6. Targeting keloids and skin fibrosis by inhibitors of DP IV and related enzymes
6.1. The cytokine TGF-beta1 in the pathogenesis of keloids and fibrosis
6.2. The effects of DP IV inhibitors LZNT and LZNP on skin fibroblast biology in vitro
6.3. In vivo effects in a mouse model of skin fibrosis
7. Role of DP IV and APN in skin cancer
7.1. Melanoma
7.2. Other skin cancers
8. Summary and Perspective
9. Acknowledgements
10. References

1. ABSTRACT

Skin cells express dipeptidyl peptidase IV (DP IV) and aminopeptidase N (APN) and their related molecules of the DP IV-like family DP2, DP6, DP8, DP9 and fibroblast activation protein (FAP), as well as the cytoplasmic alanyl aminopeptidase (cAAP). The inhibitors of DP IV-like activity, Lys(Z(NO2))-thiazolidide (LZNT) and Lys(Z(NO2))-pyrrolidide (LZNP), and the APN inhibitors actinonin and bestatin affect proliferation, differentiation and cytokine production in sebocytes and keratinocytes, which are involved in the initiation of acne. Furthermore, they suppress proliferation of Propionibacterium acnes-stimulated T cells ex vivo and induce an anti-inflammatory cytokine profile. In the mouse tail model of psoriasis they have a pro-differentiative effect. In addition, these inhibitors suppress skin fibroblast proliferation, whereas only inhibition of DP IV-like activity decreases TGF-beta1 expression and abrogates the TGF-beta1 mediated stimulatory effects on TGF-beta1 and fibronectin production, collagen synthesis and matrix deposition in these cells. Targeting enzyme activity of DP IV and APN and their related molecules might be a novel approach for the treatment of acne, psoriasis or keloids.