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Neuromedin Elicits Cytokine Release in Murine Th2-Type T Cell Clone D10.G4.1

Eric N. Johnson^1,*, Edward R. Appelbaum, Donald C. Carptenter^¶, Richard F. Cox^*, Jyoti Disa, James J. Foley^¶, Sujoy K. Ghosh, Diane P. Naselsky, Mark A. Pullen, Henry M. Sarau^¶, Samuel R. Scheff, Klaudia M. Steplewski^||, Meirav Zaks-Zilberman and Nambi Aiyar

Departments of ^* High Throughput Biology and Genomic and Proteomic Sciences, GlaxoSmithKline, Research Triangle Park, NC 27709; Cardiovascular and Urogenital Center for Excellence in Drug Discovery, Protein Agents and Human Gene Therapy, and ^¶ Respiratory and Immunology Centre for Excellence in Drug Discovery, GlaxoSmithKline, King of Prussia, PA 19405; and ^|| Genomic and Proteomic Sciences, GlaxoSmithKline, Collegeville, PA 19426

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 ¹²⁵I-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 Ca²⁺ concentration (EC₅₀ 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.

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