The CC chemokine antagonist Met-RANTES inhibits eosinophil effector functions through the chemokine receptors CCR1 and CCR3.
Eosinophils are predominant effector cells not only in allergic diseases but also in connective tissue diseases. The recruitment of eosinophils to the site of inflammation and release of reactive oxygen species leading to tissue damage and propagation of the inflammatory response are mediated by chemokines. Thus, agents that would be able to inhibit or antagonize chemokine-induced eosinophil activation are interesting as therapeutical agents. We describe the effect of a chemokine receptor antagonist, Met-RANTES, on human eosinophil effector functions in response to RANTES, monocyte chemoattractant protein (MCP)-3 and eotaxin. Met-RANTES was able to inhibit dose-dependently [Ca2+]i transients in eosinophils following stimulation with RANTES, MCP-3 and eotaxin. Whereas maximal and half-maximal inhibitory effect of Met-RANTES following stimulation with RANTES and MCP-3 were observed at 2 micrograms/ml and 1 microgram/ml, respectively, maximal and half-maximal inhibitory effects of Met-RANTES in response to eotaxin were detected at 10 micrograms/ml and 3 micrograms/ml. Moreover, eotaxin-induced [Ca2+]i transients were only half reduced at a Met-RANTES concentration at which RANTES and MCP-3 were completely blocked. Besides its effect on [Ca2+]i transients, Met-RANTES dose-dependently inhibited actin polymerization in eosinophils following chemokine stimulation. Whereas Met-RANTES totally inhibited RANTES- and MCP-3-induced actin polymerization at 5 micrograms/ml, the eotaxin-induced response was only reduced by 50%. However, Met-RANTES inhibited dose-dependently the release of reactive oxygen species in response to RANTES, MCP-3 and eotaxin. Again, eotaxin-induced release of reactive oxygen species, however, was only half reduced at a Met-RANTES concentration (10 micrograms/ml) at which RANTES and MCP-3 were completely blocked. The results of this study show that (1) Met-RANTES is an effective and powerful antagonist of effector functions of human eosinophils following stimulation with RANTES, MCP-3 and eotaxin; (2) Met-RANTES seems to be able to antagonize the response of eosinophils through chemokine receptor 1 (CCR1) preferentially to CCR3; (3) Met-RANTES antagonizes eosinophil but not neutrophil effector functions and might be therefore of interest for a new therapeutical approach to prevent the invasion and destructive power of eosinophils in diseases that are accompanied by eosinophil infiltration such as allergic asthma and connective tissue diseases.
Elsner
J
J
Hannover Medical School, Department of Dermatology, Germany. 101346.3021@compuserve.com
Petering
H
H
Höchstetter
R
R
Kimmig
D
D
Wells
T N
TN
Kapp
A
A
Proudfoot
A E
AE
D000199:Actins / Q000037:antagonists & inhibitors / Q000097:blood; D002118:Calcium / Q000097:blood; D018946:Chemokine CCL5 / Q000031:analogs & derivatives* / Q000494:pharmacology; D019742:Chemokines, CC / Q000037:antagonists & inhibitors* / Q000097:blood; D004804:Eosinophils / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D009504:Neutrophils / Q000187:drug effects; D011108:Polymers / Q000378:metabolism; D054389:Receptors, CCR1; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000097:blood / Q000187:drug effects*
D000199:Actins; C515300:CCR1 protein, human; C515350:CCR3 protein, human; D018946:Chemokine CCL5; D019742:Chemokines, CC; D011108:Polymers; C108335:RANTES, Met-; D054389:Receptors, CCR1; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D002118:Calcium