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

Citation
Rjb. Nibbs et al., 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, J IMMUNOL, 164(3), 2000, pp. 1488-1497
Citations number
53
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Immunology
Journal title
JOURNAL OF IMMUNOLOGY
ISSN journal
0022-1767 → ACNP
Volume
164
Issue
3
Year of publication
2000
Pages
1488 - 1497
Database
ISI
SICI code
0022-1767(20000201)164:3<1488:CCR3AB>2.0.ZU;2-X
Abstract
Allergic reactions are characterized by the infiltration of tissues by acti vated eosinophils, Th2 lymphocytes, and basophils, The beta-chemokine recep tor CCR3, which recognizes the ligands eotaxin, eotaxin-2, monocyte chemota ctic protein (MCP) 3, MCP4, and RANTES, plays a central role in this proces s, and antagonists to this receptor could have potential therapeutic use in the treatment of allergy. We describe here a potent and specific CCR3 anta gonist, called Met-chemokine beta 7 (Ck beta 7), that prevents signaling th rough this receptor and, at concentrations as low as I nM, can block eosino phil chemotaxis induced by the most potent CCR3 ligands. Met-Ck beta 7 is a more potent CCR3 antagonist than Met- and aminooxgyentane (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 leu kocyte infiltration associated with allergic inflammation. Met-Ck beta 7 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 unmodifie d MIP4 protein, which is known to act as a T cell chemoattractant, also exh ibits this CCR3 antagonistic activity, although to a lesser extent than Met -Ck beta 7, but to a level that mag be of physiological relevance. MIP4 may therefore use chemokine receptor agonism and antagonism to control leukocy te movement in vivo. The enhanced activity of Met-Ck beta 7 is due to the a lteration of the extreme N-terminal residue from an alanine to a methionine .