Cleavage by CD26/dipeptidyl peptidase IV converts the chemokine LD78beta into a most efficient monocyte attractant and CCR1 agonist.
Chemokines are proinflammatory cytokines that play a role in leukocyte migration and activation. Recent reports showed that RANTES (regulated on activation normal T-cell expressed and secreted chemokine), eotaxin, macrophage-derived chemokine (MDC), and stromal cell-derived factor-1 (SDF-1) are NH(2)-terminally truncated by the lymphocyte surface glycoprotein and protease CD26/dipeptidyl peptidase IV (CD26/DPP IV). Removal of the NH(2)-terminal dipeptide resulted in impaired inflammatory properties of RANTES, eotaxin, MDC, and SDF-1. The potential CD26/DPP IV substrate macrophage inflammatory protein-1beta (MIP-1beta) and the related chemokine, LD78alpha (ie, one of the MIP-1alpha isoforms), were not affected by this protease. However, CD26/DPP IV cleaved LD78beta, a most potent CCR5 binding chemokine and inhibitor of macrophage tropic human immunodeficiency virus-1 (HIV-1) infection, into LD78beta(3-70). Naturally truncated LD78beta(3-70), but not truncated MIP-1beta, was recovered as an abundant chemokine form from peripheral blood mononuclear cells. In contrast to all other chemokines processed by CD26/DPP IV, LD78beta(3-70) had increased chemotactic activity in comparison to intact LD78beta. With a minimal effective concentration of 30 pmol/L, LD78beta(3-70) became the most efficient monocyte chemoattractant. LD78beta(3-70) retained its high capacity to induce an intracellular calcium increase in CCR5-transfected cells. Moreover, on CCR1 transfectants, truncated LD78beta(3-70) was 30-fold more potent than intact LD78beta. Thus, CD26/DPP IV can exert not only a negative but also a positive feedback during inflammation by increasing the specific activity of LD78beta. CD26/DPP IV-cleaved LD78beta(3-70) is the most potent CCR1 and CCR5 agonist that retains strong anti-HIV-1 activity, indicating the importance of the chemokine-protease interaction in normal and pathologic conditions. (Blood. 2000;96:1674-1680)
Proost
P
P
Laboratory of Molecular Immunology, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium. paul.kroost@rega.kuleuven.ac.be
Menten
P
P
Struyf
S
S
Schutyser
E
E
De Meester
I
I
Van Damme
J
J
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D002633:Chemotaxis / Q000187:drug effects; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D020033:Protein Isoforms / Q000138:chemical synthesis / Q000302:isolation & purification / Q000494:pharmacology; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000819:agonists* / Q000502:physiology; D015398:Signal Transduction
C515300:CCR1 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D010446:Peptide Fragments; D020033:Protein Isoforms; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D018819:Dipeptidyl Peptidase 4; D002118:Calcium