RANTES and related chemokines activate human basophil granulocytes through different G protein‐coupled receptors

Abstract

Chemotactic cytokines related to interleukin‐8 (IL‐8; CXC‐chemokines) or monocyte chemotactic protein‐1 (MCP‐1; CC‐chemokines) have been shown to stimulate human basophils, and are considered important tissue‐derived mediators of inflammation. We have studied the effects of four CC‐chemokines and show that MCP‐1, RANTES (regulated on activation, normal T expressed and secreted) and macrophage inflammatory protein‐lα (MlP‐lα) are potent basophil agonists inducing a rapid change of cytosolic free calcium ([Ca²⁺]i), the release of histamine and sulfido‐leukotrienes, and chemotaxis. MCP‐1 was the most potent stimulus of release, and the only chemokine that induced marked exocytosis in basophils without pretreatment with interleukin‐3. RANTES was the strongest stimulus of chemotaxis, but only a moderate stimulus of release. MIP‐lα elicited relatively weak chemotaxis and release responses, but was effective at considerably lower concentrations than MCP‐1 and RANTES. MIP‐1β, by contrast, despite its high homology to MlP‐lα, was totally inactive. Normodense human eosinophils, tested for comparison, responded in a similar fashion to RANTES and MIP‐lα, but were unresponsive to MCP‐1 and MIP‐lβ. All CC‐chemokines except MIP‐lβ induced a similar rapid and transient rise of [Ca²⁺]| that was sensitive to pertussis toxin, indicating that they activate basophils via G‐protein‐coupled receptors. Cross‐desensensitization experiments indicate that basophils bear different CC‐chemokine receptors. Some interact selectively with MCP‐1 or RANTES, while others are shared by RANTES and MlP‐lα.