title: Deletion of the NH2-terminal residue converts monocyte chemotactic protein 1 from an activator of basophil mediator release to an eosinophil chemoattractant.
abstract: 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.
authors.affiliation: Institute of Immunology and Allergology, University Hospital, Bern, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Weber
authors.forename: M
authors.initials: M
authors.lastname: Uguccioni
authors.forename: M
authors.initials: M
authors.lastname: Baggiolini
authors.forename: I
authors.initials: I
authors.lastname: Clark-Lewis
authors.forename: C A
authors.initials: CA
authors.lastname: Dahinden
mesh_terms: 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
chemical_list: D000199:Actins; D018932:Chemokine CCL2; D017997:Leukotriene C4; D002118:Calcium