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

Eur J Immunol. 2001 Jul;31(7):2170-8. doi: 10.1002/1521-4141(200107)31:7<2170::aid-immu2170>3.0.co;2-d.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Calcium Signaling
  • Cell Line
  • Cells, Cultured
  • Chemokine CCL3
  • Chemokine CCL4
  • Chemotaxis, Leukocyte*
  • Cricetinae
  • Eosinophils / immunology
  • HIV-1 / drug effects*
  • Humans
  • K562 Cells
  • Macrophage Inflammatory Proteins / metabolism*
  • Macrophage Inflammatory Proteins / pharmacology*
  • Neutrophils / immunology
  • Protein Isoforms / metabolism
  • Protein Isoforms / pharmacology
  • Protein Processing, Post-Translational
  • Receptors, CCR1
  • Receptors, CCR3
  • Receptors, CCR5 / metabolism
  • Receptors, Chemokine / metabolism*
  • Virus Replication / drug effects

Substances

  • CCR1 protein, human
  • CCR3 protein, human
  • Chemokine CCL3
  • Chemokine CCL4
  • Macrophage Inflammatory Proteins
  • Protein Isoforms
  • Receptors, CCR1
  • Receptors, CCR3
  • Receptors, CCR5
  • Receptors, Chemokine