Diverging binding capacities of natural LD78beta isoforms of macrophage inflammatory protein-1alpha to the CC chemokine receptors 1, 3 and 5 affect their anti-HIV-1 activity and chemotactic potencies for neutrophils and eosinophils.
Recently, the LD78beta isoform of the CC chemokine macrophage inflammatory protein (MIP)-1alpha was shown to efficiently chemoattract lymphocytes and monocytes and to inhibit infection of mononuclear cells by R5 HIV-1 strains. We have now demonstrated that after cleavage of the NH2-terminal Ala-Pro dipeptide by CD26, LD78beta(3 - 70) became the most potent chemokine blocking HIV-1. LD78beta(3 - 70) competed tenfold more efficiently than LD78beta(1 - 70) with [125I] RANTES for binding to the CC chemokine receptors CCR5 and CCR1. Contrary to LD78alpha, LD78beta(1 - 70) at 30 ng/ml efficiently competed with [125I] RANTES for binding to CCR3 and mobilized calcium in CCR3 transfectants, whereas LD78beta(3 - 70) showed a 30-fold decrease in CCR3 affinity compared to LD78beta(1 - 70). This demonstrates the importance of the penultimate proline in LD78beta(1 - 70) for CCR3 recognition. Both LD78beta isoforms efficiently chemoattracted eosinophils from responsive donors. In contrast, only the CCR3 agonist LD78beta(1 - 70) and not LD78beta(3 - 70), induced calcium increases in eosinophils with low levels of CCR1. In responder neutrophils, LD78beta(3 - 70) elicited calcium fluxes at a 30-fold lower dose (10 ng/ml) compared to intact LD78beta and LD78alpha, whereas the three MIP-1alpha isoforms were equipotent neutrophil chemoattractants. Taken together, both LD78beta isoforms are potent HIV-1 inhibitors (CCR5) and activators for neutrophils (CCR1) and eosinophils (CCR1, CCR3), affecting infection and inflammation.
Struyf
S
S
Laboratory of Molecular Immunology, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium.
Menten
P
P
Lenaerts
J P
JP
Put
W
W
D'Haese
A
A
De Clercq
E
E
Schols
D
D
Proost
P
P
Van Damme
J
J
D000818:Animals; D016466:CHO Cells; D020013:Calcium Signaling; D002460:Cell Line; D002478:Cells, Cultured; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D002634:Chemotaxis, Leukocyte; D006224:Cricetinae; D004804:Eosinophils / Q000276:immunology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D020014:K562 Cells; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism* / Q000494:pharmacology*; D009504:Neutrophils / Q000276:immunology; D020033:Protein Isoforms / Q000378:metabolism / Q000494:pharmacology; D011499:Protein Processing, Post-Translational; D054389:Receptors, CCR1; D054397:Receptors, CCR3; D019713:Receptors, CCR5 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects
C515300:CCR1 protein, human; C515350:CCR3 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D020033:Protein Isoforms; D054389:Receptors, CCR1; D054397:Receptors, CCR3; D019713:Receptors, CCR5; D019707:Receptors, Chemokine