Human Molecular Genetics Advance Access originally published online on April 6, 2006
Human Molecular Genetics 2006 15(10):1667-1679; doi:10.1093/hmg/ddl090
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Neuropeptide S and G protein-coupled receptor 154 modulate macrophage immune responses
1Department of Medical Genetics, Biomedicum Helsinki and 2Department of Pathology, University of Helsinki, Helsinki, Finland, 3Finnish Institute of Occupational Health, Helsinki, Finland, 4Swiss Institute of Allergy and Asthma Research, Davos, Switzerland, 5Department of Allergy, Helsinki University Central Hospital, Helsinki, Finland, 6Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland, 7Department of Biosciences and Nutrition at Novum and Clinical Research Centre, Karolinska Institutet, 14157 Huddinge, Sweden and 8GeneOS Ltd, Helsinki, Finland
* To whom correspondence should be addressed. Tel: +46 86089158; Fax: +46 87745538; Email: juha.kere{at}biosci.ki.se
Received January 25, 2006; Accepted March 29, 2006
G protein-coupled receptor 154 (GPR154) is a recently discovered asthma susceptibility gene upregulated in the airways of asthma patients. We previously observed increased pulmonary mRNA expression of the murine ortholog Gpr154 in a mouse model of ovalbumin (OVA)-induced inflammation. However, the expression profile of GPR154 in leukocytes and the cellular functions of the receptor and its endogenous agonist neuropeptide S (NPS) have remained unidentified. Here, we characterized the mRNA expression of NPS and GPR154 by using real-time RT–PCR in fractionated human blood cells and in peripheral blood mononuclear cells (PBMCs) with monocyte or T cell activation. The expression of GPR154 in leukocytes was further confirmed by immunoblotting experiments and immunohistochemical staining of human sputum samples. Additionally, we characterized the expression of GPR154 in the lung tissue samples and in the bronchoalveolar lavage (BAL) fluid of OVA sensitized and challenged BALB/c mice. In human blood and sputum cells, monocyte/macrophages and eosinophils were identified as GPR154-positive cells. In PBMCs, monocyte activation with LPS but not T cell activation with anti-CD3/CD28 antibodies resulted in increased NPS and GPR154 expression. In the lung tissue samples and in the BAL fluid of OVA-challenged mice, GPR154 expression was upregulated in alveolar macrophages in comparison to controls. In the mouse macrophage RAW 264.7 cell line, NPS-stimulated G
s- and Gq-dependent phagocytosis of Escherichia coli. The results show that GPR154 is upregulated in macrophages after antigen challenge and that NPS is capable of inducing phagocytosis of unopsonized bacteria.
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