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The data presented, demonstrate for the first time PEP turnover of HN by a limited postcysteine as well as the expected post-proline proteolysis demonstrated in cell extract resulting in the inactivation of this potentially apoptosis-related factor. These findings lead to the hypothesis of a PEP-mediated control of HN homeostasis maintaining neuronal cell survival. This implicates a novel use of PEP inhibitors potentially preventing intracellular HN digestion. Consequently, PEP-inhibition might be a new target for apoptosis prevention.

This study further uncovered a so far unknown enzymatic specificity for a post-cysteine cleavage of the mammalian exopeptidases DP2, DP4, DP8 and DP9 and the endopeptidase PEP.

FAP and DPIV overexpression in the HEK293 cell line reduced cell adhesion, migration and invasion on ECM components, increased proliferation and promoted apoptosis, independently of enzyme activity. These observations may aid an understanding of the roles of FAP and DPIV in tissue remodeling.

Incretin based therapies for type 2 diabetes mellitus are quite promising. Presently, basic research places both GIP and GLP-1 based approaches on an equal standing. Recently, there has been renewed interest into the physiology of GIP in humans, and thus it is possible that DP IV resistant GIP analogues will be administered to human diabetics, perhaps reconciling differences between clinical and pre-clinical studies. Development of injection-delivered GLP-1 derivatives continues to meet expectations as a therapeutic option for the future. Particular attention to severity of diabetes and age must be considered when examining the effectiveness of either GIP or GLP-1 based analogues in human patients. Despite some uncertainties as to the precise mediators of DP IV inhibitors, data from mouse models indicate that the beneficial effects are conveyed by the known incretin hormones. Predictions of the relative contributions of GIP and GLP-1 to the glucose lowering activity of DP IV inhibition have been made, however, experimental data is required for conclusive resolution of this point. Only specifically designed studies can answer this question using selective antagonists of either the GIP or GLP-1 receptor, alone or in combination, in conjunction with DP IV inhibitors in healthy and diabetic humans.

In summary these results strongly support the idea that AAPs and DPIV represent a promising target complex for the pharmacological therapy of T cell-mediated diseases by preserving and enhancing endogenous immunosuppressive mechanisms. Whereas inhibitors of AAPs appear to preferentially act on CD4CD25 regulatory T cells by preserving their immunosuppressive activity via enhanced expression of immunosuppressive cytokines and FOXP3, inhibition of DPIV leads to increased production/release of TGF-β1 and inhibition of cellular proliferation of predominantly activated effector T cells. Thus, specific inhibition of DPIV and AAPs via small molecular compounds provides a new approach for the pharmacological treatment of autoimmune and inflammatory diseases that simultaneously interferes with two major axis of T cell function.

In summary these results strongly support the idea that AAPs and DPIV represent a promising target complex for the pharmacological therapy of T cell-mediated diseases by preserving and enhancing endogenous immunosuppressive mechanisms. Whereas inhibitors of AAPs appear to preferentially act on CD4CD25 regulatory T cells by preserving their immunosuppressive activity via enhanced expression of immunosuppressive cytokines and FOXP3, inhibition of DPIV leads to increased production/release of TGF-β1 and inhibition of cellular proliferation of predominantly activated effector T cells. Thus, specific inhibition of DPIV and AAPs via small molecular compounds provides a new approach for the pharmacological treatment of autoimmune and inflammatory diseases that simultaneously interferes with two major axis of T cell function.

In summary these results strongly support the idea that AAPs and DPIV represent a promising target complex for the pharmacological therapy of T cell-mediated diseases by preserving and enhancing endogenous immunosuppressive mechanisms. Whereas inhibitors of AAPs appear to preferentially act on CD4CD25 regulatory T cells by preserving their immunosuppressive activity via enhanced expression of immunosuppressive cytokines and FOXP3, inhibition of DPIV leads to increased production/release of TGF-β1 and inhibition of cellular proliferation of predominantly activated effector T cells. Thus, specific inhibition of DPIV and AAPs via small molecular compounds provides a new approach for the pharmacological treatment of autoimmune and inflammatory diseases that simultaneously interferes with two major axis of T cell function.

The presented data provide evidence that DP IV is expressed on human sebocytes and most likely involved in regulation of sebocyte proliferation and cytokine production. The aminopeptidase inhibitors Lys[Z(NO)]-thiazolidide and Lys[Z(NO)]-pyrrolidide suppress proliferation of three cells types involved in acne initiation; moreover, they induce the anti-inflammatory cytokine IL-1RA in sebocytes and keratinocytes being capable to follicular hyperkeratosis, and they up-regulate the immunosuppressive cytokine transforming growth factor-β1 in -stimulated T cells.

In summary, DP IV inhibitors affect proliferation, differentiation and inflammation processes in acne-involved cells in a therapeutic manner (Table 1). Thus they might in the future act as promising new agents for acne therapy.

Deregulation of DPP-IV-like activity was observed in synovial fluid and blood plasma of patients with RA and PsA. The cellular source of soluble DPP-IV-like enzymatic activity remains unclear.

Our results suggest significant contribution of intracellular DASH molecules to the total DPP-IV-like enzymatic activity, at least in FMNC from rheumatoid arthritis patients and in BMNC from both rheumatoid arthritis and osteoarthritis.

DASH subcellular distribution was different in FMNC in patients with rheumatoid arthritis compared to degenerative osteoarthritis.

Altered expression pattern and resulting distorted properties of whole DASH enzymatic activity in both systemic—blood—as well as local—joint—environments may impair processing of mediators involved in the inflammatory processes.

Together, DASH molecules, due to their enzymatic activity, may participate on the pathogenesis of RA and PsA and deserve attention as possible future therapeutic targets

In conclusion, these findings from and studies demonstrate that DP IV activity associated with CD26 plays an important role in the activation of autoreactive T cells. Moreover, inhibition of both DP IV/CD26 and APN/CD13 activity and provides a new approach to modulate T cell functions and tissue-specific autoimmunity in the CNS. These results may have important implications for the treatment of human diseases with a putative autoimmune pathogenesis. At present, major research efforts are directed at the investigation of DP IV/CD26 and APN/CD13 as potentially powerful and safe pharmacological targets. Our preliminary data raise the possibility that simultaneous inhibition of DP IV/CD26 and APN/CD13 may be advantageous over targeting a single ectopeptidase, and support the development of inhibitors with dual specificities for both ectopeptidases.

In summary, the present study demonstrates a critical role for CD26/DP IV in balancing Th1 immune responses. We observed a deregulation of the autoimmune process in EAE , the prototypic model of an immune-mediated CNS disorder. Our results support the notion of a critical regulatory role for the CD26/DP IV molecule within the immune system.