No abstract

Chemokines, binding their various G protein-coupled receptors, lead the way for leukocytes in health and inflammation. Yet chemokine receptor expression is not limited to leukocytes. Accordingly, chemokines are remarkably pleiotropic molecules involved in a range of physiological as well as pathological processes. For example, the CXCR3 chemokine receptor is expressed on activated T lymphocytes, dendritic cells and natural killer cells, but also fibroblasts and smooth muscle, epithelial and endothelial cells. In men, these cells express either CXCR3A, its splice variant CXCR3B or a balanced combination of both. The CXCR3 ligands, activating both receptor variants, include CXCL4, CXCL4L1, CXCL9, CXCL10 and CXCL11. Upon CXCR3A activation these ELR-negative CXC chemokines mediate chemotactic and proliferative responses, for example in leukocytes. In contrast, CXCR3B induces anti-proliferative and anti-migratory effects, as exemplified by angiostatic effects on endothelial cells. Taken together, the unusual and versatile characteristics of CXCR3 and its ligands form the basis for their pertinent involvement in a myriad of diseases. In this review, we discuss the presence and function of all CXCR3 ligands in various malignant, angiogenic, infectious, inflammatory and other disorders. By extension, we have also elaborated on the potential therapeutic applicability of CXCR3 ligand administration or blockade, as well as their additional value as predictive or prognostic biomarkers. This review illustrates the multifunctional, intriguing character of the various CXCR3-binding chemokines.

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...