Deletion of the NH2-terminal residue converts monocyte chemotactic protein 1 from an activator of basophil mediator release to an eosinophil chemoattractant.
Chemotactic cytokines of the CC subfamily (CC chemokines) are considered as major mediators of allergic inflammation owing their actions on basophil and eosinophil leukocytes. The monocyte chemotactic protein (MCP) 1 is a potent inducer of mediator release from basophils but is inactive on eosinophils. To obtain information on the structural determinants of the activities of MCP-1, we have synthesized several NH2-terminally truncated analogues and tested their effects on basophils and eosinophils. Through deletion of the NH2-terminal residue, MCP-1(2-76) was obtained, which was a potent activator of eosinophils, as assessed by chemotaxis, cytosolic free Ca2+ changes, actin polymerization, and that induction of the respiratory burst. In contrast, the activity of MCP-1(2-76) on basophil leukocytes was dramatically decreased (50-fold) compared with that of full-length MCP-1. Deletion of the next residue led to total loss of activity on eosinophil and basophil leukocytes. Analogues with three or four residue deletions, MCP-1(4-76) and MCP-1(5-76), were again active on both cells, whereas all further truncation analogues, MCP-1(6-76) through MCP-1(10-76), were inactive. Thus, a minimal structural modification can change receptor and target cell selectivity of MCP-1. Our observations indicate that the recognition sites of CC chemokine receptors on eosinophils and basophils are similar, although they discriminate between MCP-1 and MCP-1(2-76) and suggest NH2-terminal processing as a potential mechanism for the regulation of CC chemokine activities.
Weber
M
M
Institute of Immunology and Allergology, University Hospital, Bern, Switzerland.
Uguccioni
M
M
Baggiolini
M
M
Clark-Lewis
I
I
Dahinden
C A
CA
D000199:Actins / Q000378:metabolism; D001491:Basophils / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D018932:Chemokine CCL2 / Q000031:analogs & derivatives*; D002634:Chemotaxis, Leukocyte; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000187:drug effects*; D006636:Histamine Release; D006801:Humans; D017997:Leukotriene C4 / Q000378:metabolism; D016897:Respiratory Burst; D017384:Sequence Deletion; D013329:Structure-Activity Relationship
D000199:Actins; D018932:Chemokine CCL2; D017997:Leukotriene C4; D002118:Calcium