Recent insights into the role of dipeptidyl aminopeptidase IV (DPIV) and aminopeptidase N (APN) families in immune functions

被引:57
作者
Ansorge, Siegfried [1 ]
Bank, Ute [1 ]
Heimburg, Anke [1 ]
Helmuth, Martin [1 ]
Koch, Gudrun [1 ]
Tadje, Janine [1 ]
Lendeckel, Uwe [2 ]
Wolke, Carmen [2 ]
Neubert, Klaus [3 ]
Faust, Juergen [3 ]
Fuchs, Petra [3 ]
Reinhold, Dirk [4 ]
Thielitz, Anja [5 ]
Taeger, Michael [1 ]
机构
[1] IMTM GmbH, D-39120 Magdeburg, Germany
[2] Otto Von Guericke Univ, Inst Expt Internal Med, Magdeburg, Germany
[3] Univ Halle Wittenberg, Inst Biochem & Biotechnol, Dept Nat Sci 1, Halle, Germany
[4] Otto Von Guericke Univ, Inst Mol & Clin Immunol, Magdeburg, Germany
[5] Otto Von Guericke Univ, Univ Clin Dermatol & Venerol, Magdeburg, Germany
关键词
aminopeptidase N (APN); cytokines; dermal diseases; dipeptidyl peptidase IV (DPIV); DPIV-like enzymes; immune system; inflammatory diseases; PETIR (TM); REGULATORY T-CELLS; PEPTIDASE-IV; ALANYL-AMINOPEPTIDASE; INHIBITION; GROWTH; SECRETION; PROLIFERATION; EXPRESSION; TGF-BETA-1; TOLERANCE;
D O I
10.1515/CCLM.2009.063
中图分类号
R446 [实验室诊断]; R-33 [实验医学、医学实验];
学科分类号
1001 ;
摘要
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-beta 1 (TGF-beta 1) 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 (TM), 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 (TM) 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.
引用
收藏
页码:253 / 261
页数:9
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