Downstream target genes of the neuropeptide S-NPSR1 pathway.
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.
Vendelin
Johanna
J
Department of Medical Genetics, Biomedicum Helsinki, University of Helsinki, Finland, and Department of Biosciences and Nutrition, Clinical Research Centre, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
Bruce
Sara
S
Holopainen
Päivi
P
Pulkkinen
Ville
V
Rytilä
Paula
P
Pirskanen
Asta
A
Rehn
Marko
M
Laitinen
Tarja
T
Laitinen
Lauri A
LA
Haahtela
Tari
T
Saarialho-Kere
Ulpu
U
Laitinen
Annika
A
Kere
Juha
J
D017209:Apoptosis; D001249:Asthma / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D001980:Bronchi / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D017931:DNA Primers / Q000235:genetics; D030541:Databases, Genetic; D006801:Humans; D053506:Matrix Metalloproteinase 10; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics* / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D043562:Receptors, G-Protein-Coupled / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism
D017931:DNA Primers; C484532:NPSR1 protein, human; D009479:Neuropeptides; D043562:Receptors, G-Protein-Coupled; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; C506531:neuropeptide S, human; D008666:Metalloendopeptidases; D053506:Matrix Metalloproteinase 10