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Signalling pathways regulating inducible nitric oxide synthase expression in human kidney epithelial cells
Department of Clinical Pharmacology, Lund University Hospital, Lund, Sweden.
Department of Clinical Pharmacology, Lund University Hospital, Lund, Sweden.ORCID iD: 0000-0002-3576-2393
Department of Clinical Pharmacology, Lund University Hospital, SE-221 85, Lund, Sweden.
2003 (English)In: European Journal of Pharmacology, ISSN 0014-2999, E-ISSN 1879-0712, Vol. 469, no 1-3, 21-28 p.Article in journal (Refereed) Published
Abstract [en]

The purpose of this study was to elucidate the signalling pathways involved in the cytokine-activated inducible nitric oxide synthase (iNOS) response in a human kidney epithelial cell line, A498. Unstimulated cells did not express iNOS. Exposure of A498 cells to a cytokine mixture consisting of interferon gamma, interleukin-1 beta and tumor necrosis factor-alpha (TNF-alpha) increased nitrite production, iNOS mRNA and protein expression. Pharmacological inhibition of tyrosine kinases, including janus kinase (JAK2), and protein kinase C (PKC) inhibited cytokine-mediated nitrite production and iNOS protein expression. The involvement of mitogen-activated protein kinases (MAPKs) was investigated. Inhibition of p38 MAPK, but not of an upstream activator of extracellular signal-regulated kinase (ERK), caused a decrease in iNOS expression and nitrite production in response to cytokines. Electrophoretic mobility shift assay of nuclear extract from cytokine-stimulated cells demonstrated a pronounced binding to a nuclear factor kappa B (NF-kappa B) sequence present in the human iNOS promoter. Furthermore, the NF-kappa B inhibitor pyrrolidinedithiocarbamate (PDTC) decreased cytokine-activated iNOS protein expression and nitrite production. The present study has demonstrated that cytokine-stimulated iNOS expression in human kidney epithelial cells involves activation of tyrosine kinases, including JAK2, PKC, p38 MAPK and NF-kappa B.

Place, publisher, year, edition, pages
2003. Vol. 469, no 1-3, 21-28 p.
Keyword [en]
MAP (mitogen-activated protein) kinase, NF-κB (nuclear factor-κB), Nitric oxide (NO), Tyrosine kinase, Urinary tract infection
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:hh:diva-15179DOI: 10.1016/S0014-2999(03)01716-3ISI: 000183427400003PubMedID: 12782181Scopus ID: 2-s2.0-0038054073OAI: oai:DiVA.org:hh-15179DiVA: diva2:419617
Available from: 2011-05-27 Created: 2011-05-27 Last updated: 2015-09-21Bibliographically approved

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CiteExportLink to record
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