RANTES and macrophage inflammatory protein 1α induce the migration and activation of normal human eosinophil granulocytes

Abstract

The cellular infiltrates of certain inflammatory processes found in parasitic infection or in allergic diseases consist predominantly of eosinophilic granulocytes, often in association with activated T cells. This suggests the existence of chemotactic agonists specific for eosinophils and lymphocyte subsets devoid of neutrophil-activating properties. We therefore examined four members of the intercrine/chemokine superfamily of cytokines (monocyte chemotactic peptide 1 [MCP-1], RANTES, macrophage inflammatory protein 1α[MIP-1α], and MIP-1β), which do not activate neutrophils, for their ability to affect different eosinophil effector functions. RANTES strongly attracted normal human eosinophils by a chemotactic rather than a chemokinetic mechanism with a similar efficacy as the most potent chemotactic myeloid cell agonist, C5a. MIP-1α also induced eosinophil migration, however, with lower efficacy. RANTES and MIP-1α induced eosinophil cationic protein release in cytochalasin B-treated eosinophils, but did not promote leukotriene C4 formation by eosinophils, even after preincubation with interleukin 3 (IL-3), in contrast to other chemotactic agonists such as C5a and formyl-methionyl-leucyl-phenylalanine (FMLP). RANTES, but not MIP-1α, induced a biphasic chemiluminescence response, however, of lower magnitude than C5a. RANTES and MIP-1α both promoted identical transient changes in intracellular free calcium concentration ([Ca2+]i), with kinetics similar to those induced by chemotactic peptides known to interact with G protein-coupled receptors. No cross-desensitization towards other peptide agonists (e.g., C5a, IL-8, FMLP) was observed, suggesting the presence of specific receptors. Despite its weaker eosinophil-activating properties, MIP-1α was at least 10 times more potent on a molar basis than RANTES at inducing [Ca2+]i changes. Interestingly, RANTES deactivated the MIP-1α-induced [Ca2+]i changes, while the RANTES response was preserved after MIP-1α stimulation. MCP-1, a potent monocyte chemoattractant and basophil agonist, as well as MIP-1β, a peptide with pronounced homology to MIP-1α, did not activate the eosinophil functions tested. Our results indicate that RANTES and MIP-1α are crucial mediators of inflammatory processes in which eosinophils predominate.