Dipeptidyl Peptidase IV (DP IV, CD26) and Aminopeptidase N (APN, CD13) as Regulators of T Cell Function and Targets of Immunotherapy in CNS Inflammation

Biton, Aliza; Bank, Ute; Täger, Michael; Ansorge, Siegfried; Reinhold, Dirk; Lendeckel, Uwe; Brocke, Stefan

doi:10.1007/0-387-32824-6_19

Cited by 5 publications

(5 citation statements)

References 48 publications

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“…Interestingly, simultaneous inhibition of both enzymes exhibited partially additive effects on the proliferation, but not cytokine production, in different cell types (Figures 3d and 6b, d; Table 1). With regard to the development of therapeutic agents, the application of an inhibitor combination might be useful, because synergistic effects have been reported on T cells in vitro (Lendeckel et al, 2003) and in vivo (Bank et al, 2006;Biton et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Inhibitors of Dipeptidyl Peptidase IV and Aminopeptidase N Target Major Pathogenetic Steps in Acne Initiation

Thielitz

Reinhold

Vetter

et al. 2007

Journal of Investigative Dermatology

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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.

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Section: Discussionmentioning

confidence: 99%

Inhibitors of Dipeptidyl Peptidase IV and Aminopeptidase N Target Major Pathogenetic Steps in Acne Initiation

Thielitz

Reinhold

Vetter

et al. 2007

Journal of Investigative Dermatology

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“…ANPEP (also known as CD13) is a membrane metalloprotease consisting of 150 kDa, and an ectoenzyme of zinc-dependent aminopeptidases (Reinhold et al, 2007; Nefla et al, 2015). Recent studies have illustrated that ANPEP could involve in many biological process, such as the regulation of antigen-presenting (Thomas et al, 1994), immunoregulation (Biton et al, 2006), intestinal cholesterol absorption (Kramer et al, 2005). The compound of human CD13 and antibody could inhibit infection and block binding of HCMV virions to susceptible cells (Soderberg et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

“…In present study, we found that lncRNA CRNG could negatively regulate the expression of ANPEP, in addition, GO biological process had shown that lncRNA CRNG may involve in virus-host interaction. APN/CD13 could also serve as a modulator to T cell and target of tissue-specific autoimmunity in the CNS (Biton et al, 2006). CD13 served as a negative regulator for activation of mast cells in vitro and in vivo (Metz and Maurer, 2007; Ghosh et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Molecular Characterization and Biological Function of a Novel LncRNA CRNG in Swine

Huang

et al. 2019

Front. Pharmacol.

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Our previous study has showed that a novel gene is differentially expressed in the liver of cyadox-fed piglets, but its sequence and function are unknown. Here, rapid amplification of cDNA ends (RACE) and bioinformatics analysis showed that the novel gene is 953 bp without protein-coding ability and locates in chromosome 11. Hence, we identified the novel gene as long non-coding RNA (lncRNA) and named it cyadox-related novel gene (CRNG). Fluorescence in situ hybridization (FISH) showed that CRNG mainly distributes in cytoplasm. Moreover, microarray assay in combination with CRNG interference and overexpression showed that the differential genes such as ANPEP, KITLG, STAT5A, FOXP3, miR-451, IL-2, IL-10, IL-6, and TNF-α are mainly involved in viral and pathogens infection and the immune-inflammatory responses in PK-15 cells. This work reveals that CRNG might play a role in preventing the host from being infected by pathogens and viruses and exerting immune regulatory effects in the cytoplasm, which may be involved in prophylaxis of cyadox in piglets.

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“…Based on the finding that synthetic inhibitors of both enzymes elicit additive to super-additive suppressing effects on DNA synthesis and proinflammatory cytokine production particularly at low inhibitor concentrations in vitro, a novel therapeutic strategy was proposed, which was termed Peptidase-targeted Immunoregulation (PETIR TM ). The hypothesized mechanism is the restoration and maintenance of immune balance directly by limiting T effector cells activation, and indirectly, by the induction of powerful endogenous immunosuppressive mechanisms, such as TGF-beta1 and regulatory T cells (70,73,112). We were recently able to demonstrate that a daily intraperitoneal or oral application of DPIV and APN inhibitors after the onset of colitis symptoms (day 4 to 7) reduces disease progression in the DSS colitis model (113).…”

Section: Effects Of Dipeptidyl Peptidase and Alanyl-aminopeptidase Inmentioning

confidence: 99%

“…The administration of GLP-2 alone was reported to reduce the severity of colitis in rodents (129), but data from Hartmann et al suggested that the administration of dipeptidyl peptidase inhibitors may enhance the intestinotrophic effects of GLP-2 (130). There are hints that various members of the DASH family may be involved in this mechanism (111,112). Interestingly, the GLP-2-induced improvement of the intestinal wound healing seems to involve TGF-beta1 mediated effects (131).…”

Section: Augmentation Of Intestinal Repair Mechanisms By Induction Anmentioning

confidence: 99%

Inflammatory bowel diseases: multiple benefits from therapy with dipeptidyl- and alanyl-aminopeptidase inhibitors

Bank¹,

Bohr²,

Reinhold³

et al. 2008

Front Biosci

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Inflammatory bowel diseases (IBD) are driven by imbalances in innate and acquired immune response. In IBD two dysregulated T cell subsets are in the focus of interest: activated effector T cells and regulatory T cells. These T cell subsets are characterized by a strong expression of the ectopeptidases dipeptidyl peptidase IV (DPIV /CD26) and aminopeptidase N (APN/CD13), which are thought to a role in the control of immune activation and in regulating cellular communication by hydrolyzing bioactive polypeptides. Since inhibitors of both enzymes were shown to be effective in limiting immune activation processes in vitro as well as in vivo, they emerged as new drug candidates for the treatment of diseases associated with an imbalanced T cell response, such as IBD. In this review we intent to throw light on the putative role of DPIV, APN and related enzymes in the regulation of immune and non-immune processes in inflammatory bowel diseases, on possible benefits from peptidase inhibitor therapy in these diseases as well on the gaps of knowledge in this field.

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Dipeptidyl Peptidase IV (DP IV, CD26) and Aminopeptidase N (APN, CD13) as Regulators of T Cell Function and Targets of Immunotherapy in CNS Inflammation

Cited by 5 publications

References 48 publications

Inhibitors of Dipeptidyl Peptidase IV and Aminopeptidase N Target Major Pathogenetic Steps in Acne Initiation

Inhibitors of Dipeptidyl Peptidase IV and Aminopeptidase N Target Major Pathogenetic Steps in Acne Initiation

Molecular Characterization and Biological Function of a Novel LncRNA CRNG in Swine

Inflammatory bowel diseases: multiple benefits from therapy with dipeptidyl- and alanyl-aminopeptidase inhibitors

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