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 eosinophil chemoattractant in guinea pig airways and skin in vivo, and stimulates both guinea pig and human eosinophils in vitro. The human C-C chemokine RANTES (30% homology with guinea pig eotaxin) stimulates human eosinophils in vitro, but does not stimulate guinea pig eosinophils, even though these cells bind 125I-RANTES. Similar concentrations of eotaxin and unlabeled RANTES competitively inhibit the binding of 125I-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 responses to eotaxin. When fura-2-loaded cells were first exposed to RANTES, which failed to elevate the intracellular calcium concentration, the response to a subsequent challenge with eotaxin was inhibited in a dose-dependent manner. Inhibition was also demonstrated when the two chemokines were added simultaneously. Another human C-C chemokine, MCP-3 (52% homology with guinea pig eotaxin), had similar inhibitory effects on the eotaxin-induced activation of guinea pig eosinophils in vitro. RANTES inhibited (111)In-eosinophil accumulation in response to intradermal eotaxin in vivo. In contrast, RANTES had no significant effect on responses to leukotriene B4 in vitro or in vivo. Thus, these experiments in the guinea pig demonstrate that human RANTES is the first prototypic antagonist of an eotaxin receptor.
National Heart and Lung Institute, Imperial College of Science, Technology and Medicine, London, United Kingdom.
S
S
Marleau
D A
DA
Griffiths-Johnson
P D
PD
Collins
Y S
YS
Bakhle
T J
TJ
Williams
P J
PJ
Jose
D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D054413:Chemokine CCL11; D018946:Chemokine CCL5 / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D054410:Chemokine CCL7; D019742:Chemokines, CC; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D016207:Cytokines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D008969:Molecular Sequence Data; D018945:Monocyte Chemoattractant Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012867:Skin / Q000187:drug effects / Q000276:immunology
C515456:CCL11 protein, human; C515450:CCL7 protein, human; C515350:CCR3 protein, human; D054413:Chemokine CCL11; D018946:Chemokine CCL5; D054410:Chemokine CCL7; D019742:Chemokines, CC; D016207:Cytokines; D018945:Monocyte Chemoattractant Proteins; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D002118:Calcium