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.