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

Abstract

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.

Role of Dipeptidyl Peptidase IV/CD26 in Inflammatory Bowel Disease

“…Considering that DPP IV/CD26 is a member of a large S9b family of structurally homologous serine proteases that possess a unique catalytic activity, and since two recent studies have demonstrated a broad tissue distribution of DPP IV-like enzyme activity in both wild type and CD26 -/-, a possible explanation of results obtained in our study could be that other DPP IV-like protease are involved in the activation of the inflammatory response in animal model of colitis (Ansorge et al, 2009;Yu et al, 2009). Furthermore, it was recently demonstrated by Yazbeck and its coworkers (Yazbeck et al, 2008) that inhibition of DPP-like activity ameliorates the severity of inflammation in experimental colitis in mice.…”

Sitagliptin, a Dipeptidyl Peptidase-IV Inhibitor, Improves Psoriasis

“…It was reported in 2009 that a new inhibitor for both CD26 and APN was developed for the treatment of inflammatory skin diseases and recruited to a clinical phase II study [8]. On the other hand, the effects of DPP-IV inhibitors on the immune system have not been extensively investigated.…”

Upregulation of CD26 expression in epithelial cells and stromal cells during wound-induced skin tumour formation

“…CD26 is proposed to function as a keratinocyte activation antigen (Novelli et al, 1996). Moreover, CD26 inhibitors, currently used to manage type-2 diabetes, are being evaluated as treatments for psoriasis (Ansorge et al, 2009). CD26 is expressed in the differentiating epidermal layers and thus the upregulation in InvEE transgenic mice is correlated with the increased number of differentiated cell layers.…”