C-C Chemokine Receptor 3 Antagonism by the β-Chemokine Macrophage Inflammatory Protein 4, a Property Strongly Enhanced by an Amino-Terminal Alanine-Methionine Swap

Abstract

Allergic reactions are characterized by the infiltration of tissues by activated eosinophils, Th2 lymphocytes, and basophils. The β-chemokine receptor CCR3, which recognizes the ligands eotaxin, eotaxin-2, monocyte chemotactic protein (MCP) 3, MCP4, and RANTES, plays a central role in this process, and antagonists to this receptor could have potential therapeutic use in the treatment of allergy. We describe here a potent and specific CCR3 antagonist, called Met-chemokine β 7 (Ckβ7), that prevents signaling through this receptor and, at concentrations as low as 1 nM, can block eosinophil chemotaxis induced by the most potent CCR3 ligands. Met-Ckβ7 is a more potent CCR3 antagonist than Met- and aminooxypentane (AOP)-RANTES and, unlike these proteins, exhibits no partial agonist activity and is highly specific for CCR3. Thus, this antagonist may be of use in ameliorating leukocyte infiltration associated with allergic inflammation. Met-Ckβ7 is a modified form of the β-chemokine macrophage inflammatory protein (MIP) 4 (alternatively called pulmonary and activation-regulated chemokine (PARC), alternative macrophage activation-associated C-C chemokine (AMAC) 1, or dendritic cell-derived C-C chemokine (DCCK) 1). Surprisingly, the unmodified MIP4 protein, which is known to act as a T cell chemoattractant, also exhibits this CCR3 antagonistic activity, although to a lesser extent than Met-Ckβ7, but to a level that may be of physiological relevance. MIP4 may therefore use chemokine receptor agonism and antagonism to control leukocyte movement in vivo. The enhanced activity of Met-Ckβ7 is due to the alteration of the extreme N-terminal residue from an alanine to a methionine.

Up-Regulation of the Chemokine CCL18 by Macrophages Is a Potential Immunomodulatory Pathway in Cutaneous T-Cell Lymphoma

“…An inhibitory function of CCL18 on other chemokine receptors has also been described by interaction of CCL18 with CCR3. 25 Expression of CCR3 and its ligands CCL11 and CCL26 has been reported in CTCL. 26,27 In addition to CTCL, CCL18 up-regulation has been described in B-cell leukemia 15 and in gastric and ovarian cancer.…”

Identification of Biologically Active Chemokine Isoforms from Ascitic Fluid and Elevated Levels of CCL18/Pulmonary and Activation-regulated Chemokine in Ovarian Carcinoma

“…CCL18/PARC was only recently described as a T-and B-cell chemoattractant, structurally most homologous to CCL3/MIP-1␣ (5, 20 -22, 40). Although CCL18/PARC has been reported to exhibit CC chemokine receptor-3 antagonistic activity (41), so far no agonistic receptor has been identified for this chemokine. Moreover, no homologue for human CCL18/PARC has been found yet in any other species.…”

Marked elevation of the chemokine CCL18/PARC in Gaucher disease: a novel surrogate marker for assessing therapeutic intervention

“…33,34 Eosinophil chemotaxis induced by the most potent CCR3 agonists, such as eotaxin and macrophage chemoattractant protein 4 (MCP-4), can be inhibited by CCL18 at concentrations as low as 10 nM. 31,32 The CCL18 plasma levels in symptomatic Gaucher patients exceed these inhibitory concentrations considerably (3-27 times). It seems likely that tissues rich in Gaucher cells contain even higher CCL18 concentrations.…”

“…31,32 CCR3 is expressed by eosinophils, Th2 cell subsets, basophils, mast cells, neural tissue, some epithelia, and CD34 ϩ progenitor cells. 33,34 Eosinophil chemotaxis induced by the most potent CCR3 agonists, such as eotaxin and macrophage chemoattractant protein 4 (MCP-4), can be inhibited by CCL18 at concentrations as low as 10 nM.…”