Unusual chemokine receptor antagonism involving a mitogen-activated protein kinase pathway.
Antagonism of chemokines on chemokine receptors constitutes a new regulatory principle in inflammation. Eotaxin (CCL11), an agonist for CCR3 and an attractant of eosinophils, basophils, and Th2 lymphocytes, was shown to act as an antagonist for CCR2, which is widely expressed on leukocytes and is essential for inflammatory responses. In this report we provide direct evidence for a novel mechanism how chemokine receptor function can be arrested by endogenous ligands. We show that binding of eotaxin to CCR2 stimulates the mitogen-activated protein kinases extracellular signal-regulated kinase 1/2 (ERK1/2). Activation of the mitogen-activated protein kinase kinase 1/2-ERK pathway is indispensable for eotaxin-mediated attenuation of CCR2 function, as inhibition of ERK phosphorylation abolishes the arresting effect. ERK is also activated by CCR2 agonists, e.g., monocyte chemoattractant protein-1 (CCL2). However, the involved pathways are different, although in either case coupling of CCR2 to pertussis toxin-sensitive heterotrimeric G proteins is necessary. The results are in agreement with the view that CCR2 could assume different activation states depending on the ligand it encounters. With respect to actin polymerization and calcium mobilization, the different activation states lead to agonistic and antagonistic responses. It is conceivable that the intracellular signal transduction pathway that is activated by eotaxin could cause an attenuation of proinflammatory responses mediated by CCR2.
Ogilvie
Patricia
P
Institute for Research in Biomedicine, Bellinzona, Switzerland.
Thelen
Sylvia
S
Moepps
Barbara
B
Gierschik
Peter
P
da Silva Campos
Ana Claudia
AC
Baggiolini
Marco
M
Thelen
Marcus
M
D000818:Animals; D002118:Calcium / Q000378:metabolism; D054413:Chemokine CCL11; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors; D019742:Chemokines, CC / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction
C515456:CCL11 protein, human; C515334:CCR2 protein, human; C515457:Ccl11 protein, mouse; C515335:Ccr2 protein, mouse; D054413:Chemokine CCL11; D018932:Chemokine CCL2; D019742:Chemokines, CC; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D019869:Phosphatidylinositol 3-Kinases; D002118:Calcium