Cleavage by CD26/dipeptidyl peptidase IV converts the chemokine LD78β 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 NH2-terminally truncated by the lymphocyte surface glycoprotein and protease CD26/dipeptidyl peptidase IV (CD26/DPP IV). Removal of the NH2-terminal dipeptide resulted in impaired inflammatory properties of RANTES, eotaxin, MDC, and SDF-1, The potential CD26/DPP IV substrate macrophage inflammatory protein-1 beta (MIP-1 beta) and the related chemokine, LD78 alpha (ie, one of the MIP-1 alpha isoforms), were not affected by this protease, However, CD26/DPP IV cleaved LD78 beta, a most potent CCR5 binding chemokine and inhibitor of macrophage tropic human immunodeficiency virus-1 (HIV-1) infection, into LD78 beta(3-70), Naturally truncated LD78 beta(3-70), but not truncated MIP-1 beta, was recovered as an abundant chemokine form from peripheral blood mononuclear cells. In contrast to all other chemokines processed by CD26/DPP IV, LD78 beta(3-70) had increased chemotactic activity in comparison to intact LD78 beta, With a minimal effective concentration of 30 pmol/L, LD78 beta(3-70) became the most efficient monocyte chemoattractant. LD78 beta(3-70) retained its high capacity to induce an intracellular calcium increase in CCR5-transfected cells. Moreover, on CCR1 transfectants, truncated LD78 beta(3-70) was 30-fold more potent than intact LD78 beta, Thus, CD26/DPP IV can exert not only a negative but also a positive feedback during inflammation by increasing the specific activity of LD78 beta. CD26/DPP IV-cleaved LD78 beta(3-70) is the most potent CCR1 and CCR5 agonist that retains strong anti-HIV-l activity, indicating the importance of the chemokine-protease interaction in normal and pathologic conditions. (Blood, (C) 2000 by The American Society of Hematology.