NATURAL TRUNCATION OF RANTES ABOLISHES SIGNALING THROUGH THE CC-CHEMOKINE RECEPTORS CCR1 AND CCR3, IMPAIRS ITS CHEMOTACTIC POTENCY AND GENERATES A CC-CHEMOKINE INHIBITOR

Selective leukocyte trafficking towards sites of inflammation is media ted by chemokines, RANTES is a CC chemokine that attracts lymphocytes, monocytes, dendritic cells, eosinophils, basophils and NK cells. A na tural form of human RANTES lacking two N-terminal residues was isolate d from stimulated sarcoma cells, fibroblasts, and leukocytes. RANTES(3 -68) showed a more than tenfold reduction in chemolactic potency for m onocytes and eosinophils. To elucidate the mechanism involved, recepto r recognition studies were performed. In cells transfected with the CC chemokine receptor (CCR) 5, the major co-receptor for macrophage-trop ic HIV-1 strains, RANTES(3-68) mobilized calcium and desensitized RANT ES(1-68)-induced calcium fluxes equally well as RANTES(1-68). However, RANTES(3-68) was ineffective on CCR1 and CCR3 transfectants. The redu ced potency of natural RANTES(3-68) by selective loss of receptor-acti vating characteristics was confirmed with recombinant RANTES(3-68). In chemotaxis assays using monocytic cells, RANTES(3-68) inhibited RANTE S(1-68), macrophage inflammatory protein-1 alpha (MIP-1 alpha), MIP-1 beta or monocyte chemotactic protein-3 (MCP-3), but not MCP-1- or MCP- 2-induced chemotaxis. Thus, a minor post-translational modification ha s a remarkable impact on the biological activities of RANTES and a pat hophysiologically induced change in the relative amounts of intact and truncated RANTES might affect the outcome of inflammation or HIV infe ction.