Diverging binding capacities of natural LD78β isoforms of macrophage inflammatory protein-1α to the CC chemokine receptors 1, 3 and 5 affect their anti-HIV-1 activity and chemotactic potencies for neutrophils and eosinophils
✍ Scribed by Sofie Struyf; Patricia Menten; Jean-Pierre Lenaerts; Willy Put; Anne D'Haese; Erik De Clercq; Dominique Schols; Paul Proost; Jo Van Damme
- Publisher
- John Wiley and Sons
- Year
- 2001
- Tongue
- English
- Weight
- 160 KB
- Volume
- 31
- Category
- Article
- ISSN
- 0014-2980
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✦ Synopsis
Recently, the LD78 g isoform of the CC chemokine macrophage inflammatory protein (MIP)-1 § 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 NH 2 -terminal Ala-Pro dipeptide by CD26, LD78 g (3-70) became the most potent chemokine blocking HIV-1. LD78 g (3-70) competed tenfold more efficiently than LD78 g (1-70) with [ 125 I] RANTES for binding to the CC chemokine receptors CCR5 and CCR1. Contrary to LD78 § , LD78 g (1-70) at 30 ng/ml efficiently competed with [ 125 I] RANTES for binding to CCR3 and mobilized calcium in CCR3 transfectants, whereas LD78 g (3-70) showed a 30-fold decrease in CCR3 affinity compared to LD78 g (1-70). This demonstrates the importance of the penultimate proline in LD78 g (1-70) for CCR3 recognition. Both LD78 g isoforms efficiently chemoattracted eosinophils from responsive donors. In contrast, only the CCR3 agonist LD78 g (1-70) and not LD78 g (3-70), induced calcium increases in eosinophils with low levels of CCR1. In responder neutrophils, LD78 g (3-70) elicited calcium fluxes at a 30-fold lower dose (10 ng/ml) compared to intact LD78 g and LD78 § , whereas the three MIP-1 § isoforms were equipotent neutrophil chemoattractants. Taken together, both LD78 g isoforms are potent HIV-1 inhibitors (CCR5) and activators for neutrophils (CCR1) and eosinophils (CCR1, CCR3), affecting infection and inflammation.