Dipeptidyl-peptidase IV/CD26 (DPP IV) is a cell-surface protease belonging to the prolyloligopeptidase family. It selectively removes the N-terminal dipeptide from peptides with proline or alanine in the second position. Apart from its catalytic activity, it interacts with several proteins, for instance, adenosine deaminase, the HIV gp120 protein, fibronectin, collagen, the chemokine receptor CXCR4, and the tyrosine phosphatase CD45. DPP IV is expressed on a specific set of T lymphocytes, where it is up-regulated after activation. It is also expressed in a variety of tissues, primarily on endothelial and epithelial cells. A soluble form is present in plasma and other body fluids. DPP IV has been proposed as a diagnostic or prognostic marker for various tumors, hematological malignancies, immunological, inflammatory, psychoneuroendocrine disorders, and viral infections. DPP IV truncates many bioactive peptides of medical importance. It plays a role in glucose homeostasis through proteolytic inactivation of the incretins. DPP IV inhibitors improve glucose tolerance and pancreatic islet cell function in animal models of type 2 diabetes and in diabetic patients. The role of DPP IV/ CD26 within the immune system is a combination of its exopeptidase activity and its interactions with different molecules. This enables DPP IV/CD26 to serve as a co-stimulatory molecule to influence T cell activity and to modulate chemotaxis. DPP IV is also implicated in HIV-1 entry, malignant transformation, and tumor invasion.

Chemokines coordinate many aspects of leukocyte migration. As chemoattractants they play an important role in the innate and acquired immune response. There is good experimental evidence that N-terminal truncation by secreted or cell surface proteases is a way of modulating chemokine action. The localization of CD26/ dipeptidyl peptidase IV on cell surfaces and in biological fluids, its primary specificity, and the type of naturally occurring truncated chemokines are consistent with such a function.We determined the steady-state catalytic parameters for a relevant selection of chemokines (CCL3b, CCL5, CCL11, CCL22, CXCL9, CXCL10, CXCL11, and CXCL12) previously reported to alter their chemotactic behavior due to CD26/dipeptidyl peptidase IV-catalyzed truncation. The results reveal a striking selectivity for stromal cell-derived factor-1␣ (CXCL12) and macrophage-derived chemokine (CCL22). The kinetic parameters support the hypothesis that CD26/dipeptidyl peptidase IV contributes to the degradation of certain chemokines in vivo. The data not only provide insight into the selectivity of the enzyme for specific chemokines, but they also contribute to the general understanding of CD26/dipeptidyl peptidase IV secondary substrate specificity.

The interferon (IFN)-inducible chemokines, specifically, IFN-␥-inducible protein-10 (IP-10), monokine induced by IFN-␥ (Mig), and IFN-inducible T-cell ␣-chemoattractant (I-TAC), share a unique CXC chemokine receptor (CXCR3). Recently, the highly specific membrane-bound protease and lymphocyte surface marker CD26/dipeptidyl peptidase IV (DPP IV) was found to be responsible for posttranslational processing of chemokines. Removal of NH 2 -terminal dipeptides by CD26/ DPP IV alters chemokine receptor binding and signaling, and hence inflammatory and anti-human immunodeficiency virus (HIV) activities. CD26/DPP IV and CXCR3 are both markers for Th1 lymphocytes and, moreover, CD26/DPP IV is present in a soluble, active form in human plasma. This study reports that at physiologic enzyme concentrations CD26/DPP IV cleaved 50% of I-TAC within 2 minutes, whereas for IP-10 and Mig the kinetics were 3-and 10-fold slower, respectively. Processing of IP-10 and I-TAC by CD26/ DPP IV resulted in reduced CXCR3-binding properties, loss of calcium-signaling capacity through CXCR3, and more than 10-fold reduced chemotactic potency. IntroductionChemokines constitute a family of low molecular mass proteins that regulate the directed migration of specific subclasses of leukocytes during normal and inflammatory processes. [1][2][3] The cellular specificity of chemokines is determined by the restricted expression of chemokine receptors on various leukocyte cell types. 4 Chemokines are divided into subfamilies depending on the position of the first 2 cysteines in their primary sequence. The CC subfamily, with 2 adjacent cysteines, contains more than 20 different proteins that regulate the migration of monocytes, eosinophils, basophils, B and T lymphocytes, natural killer (NK) cells, and dendritic cells. The CXC chemokine subfamily, with 2 cysteines separated by one other amino acid, contains several proteins with a Glu-Leu-Arg (ELR) motif in front of the first cysteine. These ELRCXC chemokines all attract neutrophilic granulocytes to sites of inflammation. The CXC chemokines without an ELR motif can attract monocytes and B or T lymphocytes. Three of the known non-ELRCXC chemokines, specifically, interferon-␥ (IFN-␥)-inducible protein-10 (IP-10 or CXCL10), monokine induced by IFN-␥ (Mig or CXCL9), and IFN-inducible T-cell ␣-chemoattractant (I-TAC or CXCL11) recognize a single CXC chemokine receptor (CXCR), namely CXCR3. 5-8 IP-10, Mig, and I-TAC attract monocytes and activated memory Th1, but not Th2, lymphocytes. 9-11 Furthermore, eosinophils and subclasses of B and NK cells express CXCR3. 11,12 In addition to their role in leukocyte migration, chemokines play a role in angiogenesis. [13][14][15][16] CXCR2 is an important receptor for the angiogenic activity of ELRCXC chemokines. 17,18 In contrast, the molecular mechanism underlying the angiostatic activity of the non-ELRCXC chemokines IP-10, Mig, and platelet factor 4 (PF-4 or CXCL4) is not completely understood. 15 In addition to CXCR1 and CXCR2 (both receptors for angiogenic ELRCXC ch...