C-C chemokine receptor 3 antagonism by the beta-chemokine macrophage inflammatory protein 4, a property strongly enhanced by an amino-terminal alanine-methionine swap.
Allergic reactions are characterized by the infiltration of tissues by activated eosinophils, Th2 lymphocytes, and basophils. The beta-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 beta 7 (Ckbeta7), 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-Ckbeta7 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-Ckbeta7 is a modified form of the beta-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-Ckbeta7, 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-Ckbeta7 is due to the alteration of the extreme N-terminal residue from an alanine to a methionine.
Nibbs
R J
RJ
Cancer Research Campaign Laboratories, Beatson Institute for Cancer Research, Glasgow, United Kingdom. r.nibbs@beatson.gla.ac.uk
Salcedo
T W
TW
Campbell
J D
JD
Yao
X T
XT
Li
Y
Y
Nardelli
B
B
Olsen
H S
HS
Morris
T S
TS
Proudfoot
A E
AE
Patel
V P
VP
Graham
G J
GJ
D000276:Adjuvants, Immunologic / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000328:Adult; D000409:Alanine / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism; D020013:Calcium Signaling / Q000276:immunology; D002464:Cell Migration Inhibition; D054413:Chemokine CCL11; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D003001:Cloning, Molecular; D016207:Cytokines / Q000378:metabolism; D004804:Eosinophils / Q000378:metabolism; D006801:Humans; D007457:Iodine Radioisotopes / Q000378:metabolism; D008024:Ligands; D008715:Methionine / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; C515456:CCL11 protein, human; C111792:CCL18 protein, human; C515350:CCR3 protein, human; D054413:Chemokine CCL11; D019742:Chemokines, CC; D016207:Cytokines; D007457:Iodine Radioisotopes; D008024:Ligands; D010446:Peptide Fragments; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; D008715:Methionine; D000409:Alanine; D002118:Calcium