Neuromedin U elicits cytokine release in murine Th2-type T cell clone D10.G4.1

被引:47
作者
Johnson, EN
Appelbaum, ER
Carptenter, DC
Cox, RF
Disa, J
Foley, JJ
Ghosh, SK
Naselsky, DP
Pullen, MA
Sarau, HM
Scheff, SR
Steplewski, KM
Zaks-Zilberman, M
Aiyar, N
机构
[1] GlaxoSmithKline Inc, Dept High Throughput Biol, Res Triangle Pk, NC 27709 USA
[2] GlaxoSmithKline Inc, Dept Genomic & Proteom Sci, Res Triangle Pk, NC 27709 USA
[3] GlaxoSmithKline Inc, Resp & Immunol Ctr Excellence Drug Discovery, King Of Prussia, PA 19405 USA
[4] GlaxoSmithKline Inc, Cardiovasc & Urogenital Ctr Excellence Drug Disco, King Of Prussia, PA 19405 USA
[5] GlaxoSmithKline Inc, Genomic & Proteom Sci, Collegeville, PA 19426 USA
[6] GlaxoSmithKline Inc, Prot Agents & Human Gene Therapy, King Of Prussia, PA 19405 USA
关键词
D O I
10.4049/jimmunol.173.12.7230
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Neuromedin U (NmU), originally isolated from porcine spinal cord and later from other species, is a novel peptide that potently contracts smooth muscle. NmU interacts with two G protein-coupled receptors designated as NmU-1R and NmU-2R. This study demonstrates a potential proinflammatory role for NmU. In a mouse Th2 cell line (D10.G4.1), a single class of high affinity saturable binding sites for (125)I-labeled NmU (K(D) 364 pM and B(max) 1114 fmol/mg protein) was identified, and mRNA encoding NmU-1R, but not NmU-2R, was present. Competition binding analysis revealed equipotent, high affinity binding of NmU isopeptides to membranes prepared from D10.G4.1 cells. Exposure of these cells to NmU isopeptides resulted in an increase in intracellular Ca(2+) concentration (EC(50) 4.8 nM for human NmU). In addition, NmU also significantly increased the synthesis and release of cytokines including IL-4, IL-5, IL-6, IL-10, and IL-13. Studies using pharmacological inhibitors indicated that maximal NmU-evoked cytokine release required functional phospholipase C, calcineurin, MEK, and PI3K pathways. These data suggest a role for NmU in inflammation by stimulating cytokine production by T cells.
引用
收藏
页码:7230 / 7238
页数:9
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