Document Detail

Recent insights into the role of dipeptidyl aminopeptidase IV (DPIV) and aminopeptidase N (APN) families in immune functions.
MedLine Citation:
PMID:  19327105     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: In the past, different research groups could show that treatment of immune cells with inhibitors of post-proline splitting dipeptidyl aminopeptidases leads to functional changes in the immune system consistent with immunosuppression. This is due to the inhibition of proliferation of lymphocytes and the production of inflammatory cytokines of the TH1, TH2, and TH17, cells as well as the induction of immunosuppressive cytokines, such as transforming growth factor-beta1 (TGF-beta1) and interleukin (IL)-1RA. Until recently, most of the effects of these inhibitors on immune functions were attributed to the inhibition of dipeptidyl aminopeptidase IV (DPIV/CD26). With the identification of new peptidases of the DPIV family (DASH) with the same or similar substrate specificity [fibroblast activation protein (FAP), DP8/9], the question arose whether and to what extent the inhibition of intracellularly localized enzymes, DP8 and DP9, contribute to the observed immunosuppression. In addition, members of the aminopeptidase N (APN) family are also involved in the regulation of immune functions. Hence, the concept of a combined targeting of both families of peptidases for treatment of inflammatory diseases is a promising strategy.
RESULTS/CONCLUSIONS: Summarizing data obtained from the usage of different non-selective and selective inhibitors of DPIV, DP8/9, FAP, and DPII, this review provides evidence that in addition to DPIV, DP8/9 also regulate the immune response via modulation of cell cycle progression and cytokine production. The strongest and most consistent effects in vitro were, however, observed with non-selective inhibitors for the suppression of DNA synthesis and cytokine production. Similar effects were provoked by APN inhibitors, which were also found to suppress DNA synthesis and the production of inflammatory cytokines in vitro. However, different mechanisms and signaling pathways appear to mediate the cellular effects resulting from the inhibition of either APN or DPIV family members. In particular, members of the APN family uniquely influence the function of CD4+CD25+ regulatory T-cells. Consequently, the concomitant inhibition of both APN and DPIV enzyme families by means of two separate inhibitors or by binary inhibitors with specificity for both enzyme families (PETIR, peptidase targeted immunoregulation) synergistically affects immune cells on the level of cell cycle regulation, suppression of TH1, TH2, and TH17 cytokines as well as the activation of regulatory T-cells. Besides leukocytes, dermal cells as sebocytes, keratinocytes, and fibroblasts are also targeted by these inhibitors. This strongly suggests a broad potential of the multiple anti-inflammatory effects of PETIR in treatment of chronic inflammatory diseases, such as autoimmune diseases, allergies, and transplant rejections, as well as of inflammatory skin diseases, such as acne, psoriasis, rosacea or atopic dermatitis. The first active dual inhibitor, IP10.C8, has been developed by IMTM for the treatment of inflammatory skin diseases and has just entered the first phase II study.
Siegfried Ansorge; Ute Bank; Anke Heimburg; Martin Helmuth; Gudrun Koch; Janine Tadje; Uwe Lendeckel; Carmen Wolke; Klaus Neubert; Jürgen Faust; Petra Fuchs; Dirk Reinhold; Anja Thielitz; Michael Täger
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Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  Clinical chemistry and laboratory medicine : CCLM / FESCC     Volume:  47     ISSN:  1434-6621     ISO Abbreviation:  Clin. Chem. Lab. Med.     Publication Date:  2009  
Date Detail:
Created Date:  2009-08-13     Completed Date:  2009-08-26     Revised Date:  2013-05-20    
Medline Journal Info:
Nlm Unique ID:  9806306     Medline TA:  Clin Chem Lab Med     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  253-61     Citation Subset:  IM    
IMTM GmbH, Magdeburg, Germany.
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MeSH Terms
Antigens, CD13 / immunology*
Dipeptidyl Peptidase 4 / immunology*
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors / pharmacology
Skin Diseases / drug therapy,  immunology
Reg. No./Substance:
0/Dipeptidyl-Peptidase IV Inhibitors; 0/Protease Inhibitors; EC, CD13; EC Peptidase 4

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