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The biological significance of the new DPIV family members DP8 and DP9 is unknown. In order to obtain correlations between cell behaviors and peptidase expression levels, DP8 and DP9 overexpression in transfected cells was quantified by expressing green fluorescent protein fusion proteins. We found that, like DPIV and FAP, cells overexpressing DP8 and DP9 exhibit behavioral changes in the presence of ECM components. We demonstrated that these effects were independent of enzyme activity, and of the RGD motif that occurs in DP9. This study is the first indication of some similarities as well as differences between DP8, DP9, DPIV and FAP in their cell biological roles.

Endothelia cells in sparse culture are migratory and increase the production of gelatinases of serine- and metallo-classes in membrane vesicles. Collectively, proteases associated with membrane vesicles degrade extracellular matrix components including type-I and type-IV collagens, laminin and fibronectin. Inhibitor studies suggest the existence of small gelatinases that were derived from these serine- and metallo-proteases. Thus, further studies are warranted to demonstrate the cooperative action of metallo- and serine proteases on cell surfaces and in extracellular vesicles during endothelial cell migration in 3D collagenous matrices, and potential proteolytic activation mechanism for these cell surface proteases.

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.

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.

Potential therapeutic applications of DPIV inhibitors have fuelled interest in understanding the biological roles of DPIV and its relatives. Such efforts are confounded by the ubiquitous expression of DPIV, inhibitor selectivity questions and the variety of identified substrates. DPIV is not essential, but is such a useful enzyme that all animal species express it. The enzyme activity’s ancient and primary function is probably nutritional, providing more complete proteolysis of food and recycled proteins. This function is unnecessary in well-fed humans. The development of selective inhibitors of proteolytic activity and identification of ligand binding activities in this gene family would lead to rapid advances in understanding the biology of the POP gene family.