The immunosuppressant cyclosporin A antagonizes human formyl peptide receptor through inhibition of cognate ligand binding

doi:10.4049/jimmunol.177.10.7050

	The immunosuppressant cyclosporin A antagonizes human formyl peptide receptor through inhibition of cognate ligand binding
	Yan, Pangke ; Nanamori, Masakatsu ; Sun, Meiling ; Zhou, Caihong ; Cheng, Ni ; Li, Na ; Zheng, Wei ; Xiao, Lihua ; Xie, Xin; Ye, Richard D.
刊名	JOURNAL OF IMMUNOLOGY
	2006-11-15
卷号	177 期号:10 页码:7050-7058
ISSN号	0022-1767
DOI	10.4049/jimmunol.177.10.7050
文献子类	Article
英文摘要	Cyclosporin A (CsA) is a fungus-derived cyclic undecapeptide with potent immunosuppressive activity. Its analog, cyclosporin H (CsH), lacks immunosuppressive function but can act as an antagonist for the human formyl peptide receptor (FPR). More recent studies have shown that CsA also inhibits fMLF-induced degranulation in differentiated HL-60 promyelocytic leukemia cells. However, it is unclear whether CsA interferes with ligand-receptor interaction, G protein activation, or other downstream signaling events. In this study we used human neutrophils, differentiated HL-60 cells, and rat basophilic leukemia (RBL)-2H3 cells expressing human FPR (RBL-FPR) to identify the action site of CsA. In functional assays, CsA inhibited fMLF-stimulated degranulation, chemotaxis, calcium mobilization, and phosphorylation of the MAPKs ERK 1/2 and the serine/threonine protein kinase Akt. CsA also blocked Trp-Lys-Tyr-Met-Val-D-Met (WKYMVm)-induced functions in RBL-FPR cells. Concentrations for half-maximal inhibition with CsA are generally 6- to 50-fold higher than that of CsH. CsA was compared with another immunosuppressant, ascomycin, relative to the inhibitory effects on FPR-mediated chemotaxis, calcium mobilization, and degranulation. In these experiments, ascomycin produced no inhibitory effects at low micromolar concentrations (1-4 mu M), whereas the inhibitory effects of CsA were prominent at comparable concentrations. Finally, CsA dose-dependently inhibited the uptake of fNle-Leu-Phe-Nie-Tyr-Lys-fluoresceine and [H-3]fMLF or [I-125]WKYMVm binding to FPR. However, CsA and CsH did not show any obvious inhibitory effect on FPR-like 1-mediated cellular functions. These results demonstrate that CsA is a selective antagonist of FPR and that its inhibition of fMLF-stimulated leukocyte activation is at the level of cognate ligand binding.
WOS关键词	N-FORMYLPEPTIDE RECEPTOR ; HUMAN NEUTROPHIL ACTIVATION ; PROTEIN-COUPLED RECEPTORS ; CHEMOATTRACTANT RECEPTORS ; POTENT ; IDENTIFICATION ; LEUKOCYTE ; ASCOMYCIN ; RELEASE ; CELLS
WOS研究方向	Immunology
语种	英语
出版者	AMER ASSOC IMMUNOLOGISTS
WOS记录号	WOS:000242009700056
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/273445]
专题	中国科学院上海药物研究所
通讯作者	Wang, Ming-Wei
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China 2.Univ Illinois, Coll Med, Dept Pharmacol, Chicago, IL 60612 USA 3.Fujian Inst Microbiol, Fujian, Peoples R China
推荐引用方式 GB/T 7714	Yan, Pangke,Nanamori, Masakatsu,Sun, Meiling,et al. The immunosuppressant cyclosporin A antagonizes human formyl peptide receptor through inhibition of cognate ligand binding[J]. JOURNAL OF IMMUNOLOGY,2006,177(10):7050-7058.
APA	Yan, Pangke.,Nanamori, Masakatsu.,Sun, Meiling.,Zhou, Caihong.,Cheng, Ni.,...&Wang, Ming-Wei.(2006).The immunosuppressant cyclosporin A antagonizes human formyl peptide receptor through inhibition of cognate ligand binding.JOURNAL OF IMMUNOLOGY,177(10),7050-7058.
MLA	Yan, Pangke,et al."The immunosuppressant cyclosporin A antagonizes human formyl peptide receptor through inhibition of cognate ligand binding".JOURNAL OF IMMUNOLOGY 177.10(2006):7050-7058.