title: Formyl peptide receptor 1 and 2 dual agonist inhibits human neutrophil chemotaxis by the induction of chemoattractant receptor cross-desensitization.
abstract: Formyl peptide receptor 1 (FPR1) and FPR2/ALX are known to control neutrophil chemotaxis in response to various ligands. In this study, we investigated the inhibitory mechanism of compound 43 (Cpd43), an FPR1 and FPR2/ALX dual agonist, on human neutrophil chemotaxis. Precedent stimulation of human peripheral blood neutrophils with Cpd43 rendered the cells unresponsive in calcium mobilization induced by interleukin-8, C5a, or leukotriene B₄. In addition, neutrophils pretreated with Cpd43 lost their chemotactic responses against these chemoattractants, wherein the expressions of chemoattractant receptors CXCR1, CXCR2, C5a receptor, and leukotriene B₄ receptor 1 on the surface of neutrophils were all diminished significantly by treatment with Cpd43. By evaluating its pharmacological effect on 341 molecules, including receptors and enzymes, we also confirmed that Cpd43 has a highly specific affinity to FPR1 and FPR2/ALX and does not show binding affinity to the other chemoattractant receptors. These results indicate a previously unrecognized inhibitory mechanism of Cpd43 on neutrophil chemotaxis: the induction of cross-desensitization of multiple chemoattractant receptors in human neutrophils through its FPR1 and FPR2/ALX dual agonism.
authors.affiliation: Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sogawa
authors.forename: Takao
authors.initials: T
authors.lastname: Ohyama
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Maeda
authors.forename: Kazuki
authors.initials: K
authors.lastname: Hirahara
mesh_terms: D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D015936:Complement C5a; D003864:Depression, Chemical; D004151:Dipeptides; D006801:Humans; D016209:Interleukin-8; D007975:Leukotriene B4; D009504:Neutrophils; D047069:Pyrazolones / Q000494:pharmacology*; D044042:Receptors, Formyl Peptide / Q000819:agonists / Q000378:metabolism*; D044067:Receptors, Lipoxin / Q000819:agonists*; D014812:Vitamin K / Q000031:analogs & derivatives
chemical_list: C446520:2-(2-hydroxyethylsulfanyl)-3-methyl-1,4-naphthoquinone; D004151:Dipeptides; C469986:FPR1 protein, human; C105101:FPR2 protein, human; D016209:Interleukin-8; D047069:Pyrazolones; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D014812:Vitamin K; D007975:Leukotriene B4; C017330:N-formylmethionylphenylalanine; D015936:Complement C5a