Amino-terminal truncation of CXCR3 agonists impairs receptor signaling and lymphocyte chemotaxis, while preserving antiangiogenic properties.
The interferon (IFN)-inducible chemokines, specifically, IFN-gamma-inducible protein-10 (IP-10), monokine induced by IFN-gamma (Mig), and IFN-inducible T-cell alpha-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. Moreover, IP-10 and I-TAC cleaved by CD26/DPP IV acted as chemotaxis antagonists and CD26/DPP IV-truncated IP-10 and Mig retained their ability to inhibit the angiogenic activity of interleukin-8 in the rabbit cornea micropocket model. These data demonstrate a negative feedback regulation by CD26/DPP IV in CXCR3-mediated chemotaxis without affecting the angiostatic potential of the CXCR3 ligands IP-10 and Mig.
Proost
P
P
Laboratory of Molecular Immunology, Rega Institute for Medical Research, Leuven, Belgium. paul.proost@rega.kuleuven.nl
Schutyser
E
E
Menten
P
P
Struyf
S
S
Wuyts
A
A
Opdenakker
G
G
Detheux
M
M
Parmentier
M
M
Durinx
C
C
Lambeir
A M
AM
Neyts
J
J
Liekens
S
S
Maudgal
P C
PC
Billiau
A
A
Van Damme
J
J
D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D019743:Chemokines, CXC / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D008214:Lymphocytes / Q000502:physiology*; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000819:agonists* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship
D020533:Angiogenesis Inhibitors; C515202:CXCL11 protein, human; C080810:CXCL9 protein, human; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D019743:Chemokines, CXC; D036341:Intercellular Signaling Peptides and Proteins; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D018819:Dipeptidyl Peptidase 4; D002118:Calcium