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

Abstract

Sllmmsr~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 1ix [MIP-ltx], and MIP-1/3), which do not activate neutrophils, for their ability to affect different eosinophil effector functions. R.ANTES 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-ltx also induced eosinophil migration, however, with lower efficacy. RANTES and MIP-lo~ 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-lencyl-phenylalanine (FMLP). RANTES, but not MIP-ltx, induced a biphasic chemiluminescence response, however, of lower magnitude than C5a. RANTES and MIP-lo~ 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-lol was at least 10 times more potent on a molar basis than R.ANTES at inducing [Ca 2+ ]i changes. Interestingly, RANTES deactivated the MIP-lcz-induced [Ca2+]i changes, while the R.ANTES response was preserved after MIP-lcz stimulation. MCP-1, a potent monocyte chemoattractant and basophil agonist, as well as MIP-1/3, a peptide with pronounced homology to MIP-lo~, did not activate the eosinophil functions tested. Our results indicate that R.ANTES and MIP-ltx are crucial mediators of inflammatory processes in which eosinophils predominate.

Role of C‐C chemokine receptors 1 and 5 and CCL3/macrophage inflammatory protein‐1α in the cutaneous Arthus reaction: possible attenuation of their inhibitory effects by compensatory chemokine production

“…CCL3, a C-C chemokine, can chemoattract neutrophils, monocytes, eosinophils, basophils, and lymphocytes, and is a ligand for both CCR1 and CCR5 [44][45][46][47][48]. CCL3 caused a dose-dependent increase in neutrophil recruitment in a dinitrofluorobenzene-induced contact hypersensitivity model [49].…”

Eosinophil-active chemokines: assessment of in vivo activity

“…In agreement with their ability to bind to and activate the CCR-3 receptor, RANTES, MCP-3, MCP-4 and eotaxin are effective activators of eosinophils in vitro (18)(19)(20)(21). Thus, these chemokines have been shown to elevate intracellular calcium levels in eosinophils and induce chemotaxis, mediator release and the production of oxygen radicals.…”

“…In addition, it is now evident that elevated levels of these chemokines are found in tissue samples obtained from patients with allergic diseases (22,23). Both MCP-2 (24) and MIP-1α (19) have also been shown to activate human eosinophils but they are considerably less effective than MCP-3, MCP-4, RANTES and eotaxin (17). MCP-2 recognizes a similar receptor to that of MCP-3 (CCR-3) but it has lower receptor affinity (24).…”

“…MIP-1α does not activate the CCR-3 receptor (22) and is likely to activate eosinophils via the CCR-1 receptor. Furthermore, there is evidence to suggest that both RANTES and MCP-3 may also activate the CCR-1 receptor in eosinophils inasmuch as RANTES-and MCP-3-induced intracellular calcium elevation in eosinophils is fully desensitized only after activation of these cells with MCP-2 (CCR-3) and MIP-1α (CCR-1) (19,24).…”

Mnk kinases in cytokine signaling and regulation of cytokine responses

“…RANTES is also secreted by platelets, macrophages, eosinophils, and fibroblasts, as well as endothelial, epithelial, and endometrial cells [42]. This chemokine functions as a chemoattractant for monocytes [43], NK cells [44], memory T cells [43], eosinophils [45] and DCs [46] and along with macrophage inhibitory protein (MIP)-1a and MIP-1b acts as an HIV suppressive factor [47]. Transcription of RANTES in activated T-cells is regulated by RANTES factor of late-activated T lymphocytes-1 (RFLAT-1), a transcription factor which binds to the RANTES promoter [48].…”