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Human Molecular Genetics Advance Access originally published online on August 22, 2006
Human Molecular Genetics 2006 15(19):2923-2935; doi:10.1093/hmg/ddl234
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Downstream target genes of the neuropeptide S–NPSR1 pathway

Johanna Vendelin1, Sara Bruce4, Päivi Holopainen1,5, Ville Pulkkinen1, Paula Rytilä6, Asta Pirskanen8, Marko Rehn8, Tarja Laitinen8, Lauri A. Laitinen7, Tari Haahtela6, Ulpu Saarialho-Kere2,9, Annika Laitinen3 and Juha Kere1,4,*

1 Department of Medical Genetics, Biomedicum Helsinki, 2 Department of Dermatology and 3 Department of Anatomy, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland, 4 Department of Biosciences and Nutrition, Clinical Research Centre, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden, 5 SIAF, Davos, Switzerland, 6 Department of Allergy and 7 Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland and 8 GeneOS Ltd, Helsinki, Finland and 9 Department of Dermatology, Karolinska Institutet at Stockholm Söder Hospital, Stockholm, Sweden

* To whom correspondence should be addressed. Tel: +358 46 86089158; Fax: +358 46 87745538; Email: juha.kere{at}biosci.ki.se

Received July 5, 2006; Accepted August 11, 2006

The neuropeptide S (NPS)–NPS receptor 1 (NPSR1) pathway has recently been implicated in the pathogenesis of asthma. The purpose of this study was to identify downstream gene targets regulated by NPSR1 upon NPS stimulation. A total of 104 genes were found significantly up-regulated and 42 down-regulated by microarray analysis 6 h after NPS administration. By Gene Ontology enrichment analysis, the categories ‘cell proliferation’, ‘morphogenesis’ and ‘immune response’ were among the most altered. A TMM microarray database comparison suggested a common co-regulated pathway, which includes JUN/FOS oncogene homologs, early growth response genes, nuclear receptor subfamily 4 members and dual specificity phosphatases. The expression of four up-regulated genes, matrix metallopeptidase 10 (MMP10), INHBA (activin A), interleukin 8 (IL8) and EPH receptor A2 (EPHA2), exhibited a significant NPS dose–response relationship as confirmed by quantitative reverse-transcriptase–PCR and for MMP10 by immunoassay. Immunohistochemical analyses revealed that MMP10 and TIMP metallopeptidase inhibitor 3 (TIMP3) were both strongly expressed in bronchial epithelium, and macrophages and eosinophils expressed MMP10 in asthmatic sputum samples. Because remodeling of airway epithelium is a feature of chronic asthma, the up-regulation of MMP10 and TIMP3 by NPS–NPSR1 signaling may be of relevance in the pathogenesis of asthma.


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