HUMAN RANTES ACTS AS A RECEPTOR ANTAGONIST FOR GUINEA-PIG EOTAXIN IN-VITRO AND IN-VIVO

The guinea pig C-C chemokine, eotaxin, is a potent and selective eosin ophil chemoattractant in guinea pig airways and skin in vivo, and stim ulates both guinea pig and human eosinophils in vitro. The human C-C c hemokine RANTES (30% homology with guinea pig eotaxin) stimulates huma n eosinophils in vitro, but does not stimulate guinea pig eosinophils, even though these cells bind I-125-RANTES. Similar concentrations of eotaxin and unlabeled RANTES competitively inhibit the binding of I-12 5-RANTES to guinea pig eosinophils, suggesting that eotaxin and RANTES share a common binding site on these cells. In the present study, we investigated the possibility that human RANTES, binding to a putative eotaxin receptor on guinea pig eosinophils, might block functional res ponses to eotaxin. When fura-a-loaded cells were first exposed to RANT ES, which Failed to elevate the intracellular calcium concentration, t he response to a subsequent challenge with eotaxin was inhibited in a dose-dependent manner. Inhibition was also demonstrated when the two c hemokines were added simultaneously. Another human C-C chemokine, MCP- 3 (52% homology with guinea pig eotaxin), had similar inhibitory effec ts on the eotaxin-induced activation of guinea pig eosinophils in vitr o. RANTES inhibited (111)ln-eosinophil accumulation in response to int radermal eotaxin in vivo. In contrast, RANTES had no significant effec t on responses to leukotriene B-4 in vitro or in vivo. Thus, these exp eriments in the guinea pig demonstrate that human RANTES is the first prototypic antagonist of an eotaxin receptor.