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Nitric oxide activates IL-6 production and expression in human renal epithelial cells
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
School of Natural Sciences, Linnaeus University, Kalmar, Sweden.
School of Natural Sciences, Linnaeus University, Kalmar, Sweden; Department of Medical Sciences, Uppsala University, Uppsala , Sweden.
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2012 (English)In: American Journal of Nephrology, ISSN 0250-8095, E-ISSN 1421-9670, Vol. 36, no 6, p. 524-530Article in journal (Refereed) Published
Abstract [en]

Background/Aims: Increased nitric oxide (NO) production or inducible form of NO synthase activity have been documented in patients suffering from urinary tract infection (UTI), but the role of NO in this infection is unclear. We investigated whether NO can affect the host response in human renal epithelial cells by modulating IL-6 production and mRNA expression.

Methods: The human renal epithelial cell line A498 was infected with a uropathogenic Escherichia coli (UPEC) strain and/or the NO donor DETA/NO. The IL-6 production and mRNA expression were evaluated by ELISA and real-time RT-PCR. IL-6 mRNA stability was evaluated by analyzing mRNA degradation by real-time RT-PCR.

Results: DETA/NO caused a significant (p < 0.05) increase in IL-6 production. Inhibitors of p38 MAPK and ERK1/2 signaling, but not JNK, were shown to significantly suppress DETA/NO-induced IL-6 production. UPEC-induced IL-6 production was further increased (by 73 ± 23%, p < 0.05) in the presence of DETA/NO. The IL-6 mRNA expression increased 2.1 ± 0.17-fold in response to DETA/NO, while the UPEC-evoked increase was pronounced (20 ± 4.5-fold). A synergistic effect of DETA/NO on UPEC-induced IL-6 expression was found (33 ± 7.2-fold increase). The IL-6 mRNA stability studies showed that DETA/NO partially attenuated UPEC-induced degradation of IL-6 mRNA.

Conclusions: NO was found to stimulate IL-6 in renal epithelial cells through p38 MAPK and ERK1/2 signaling pathways and also to increase IL-6 mRNA stability in UPEC-infected cells. This study proposes a new role for NO in the host response during UTI by modulating the transcription and production of the cytokine IL-6.

Place, publisher, year, edition, pages
Basel, Switzerland: S. Karger, 2012. Vol. 36, no 6, p. 524-530
Keywords [en]
Nitric oxide, urinary tract infections, il-6, mapk signaling, renal epithelial cells
National Category
Medical and Health Sciences Microbiology in the medical area
Research subject
Medicine
Identifiers
URN: urn:nbn:se:oru:diva-26534DOI: 10.1159/000345351ISI: 000312916200004PubMedID: 23183248Scopus ID: 2-s2.0-84869889861OAI: oai:DiVA.org:oru-26534DiVA, id: diva2:572583
Available from: 2012-11-28 Created: 2012-11-28 Last updated: 2018-01-12Bibliographically approved
In thesis
1. Uropathogenic Esherichia coli, multidrug-resistance and induction of host defense mechanisms
Open this publication in new window or tab >>Uropathogenic Esherichia coli, multidrug-resistance and induction of host defense mechanisms
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Uropathogenic Escherichia coli (UPEC) is the primary cause of urinary tract infection (UTI), which is one of the most common infections in humans. UPEC strains have acquired successful strategies to subvert the host defense and antibiotics to persist in the urinary tract. The main aim of this thesis was to investigate the host defense mechanisms during a UPEC infection in vitro.

The results showed that SOCS3, a key regulator of the immune system, was increased in bladder epithelial cells in response to a UPEC infection. In addition, UPEC decreased the phosphorylation of the SOCS3 regulated transcription factor STAT3. Nitric oxide (NO), a host-derived antimicrobial factor was shown to increase the release of IL-6 from renal epithelial cells alone or in combination with UPEC. The induction of IL-6 was mediated by ERK1/2 and p38 MAPK signaling and NO was also shown to attenuate UPEC-induced IL-6 mRNA degradation. Furthermore, extended-spectrum beta-lactamase (ESBL)-producing UPEC isolates were shown to induce higher PMN migration and ROS-production, but lower cytokine secretion from renal epithelial cells than susceptible isolates. Ineffective ceftibuten treatment of ESBL isolates induced bacterial filamentation associated with an increased release of ATP and LPS, with a subsequent enhancement of the ESBL evoked host response.

Taken together, the findings show that UPEC can induce SOCS3, a suppressor of host responses and that NO can regulate proinflammatory mediators. In addition, the data suggest that there are differences between ESBL- and non-ESBL-producing isolates ability to evoke a host response. Exposing resistant isolates to ineffective antibiotics was shown to alter the evoked host response.

Place, publisher, year, edition, pages
Örebro: Örebro universitet, 2014. p. 87
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 105
Keywords
Urinary tract infection, uropathogenic Escherichia coli, suppressor of cytokine signalling 3, nitric oxide, cytokines, extended-spectrum beta-lactamases, filamentation, IL-6
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-33556 (URN)978-91-7529-013-3 (ISBN)
Public defence
2014-05-23, Campus USÖ (Universitetssjukhuset) X-huset, Hörsal C1, Södra Grev Rosengatan, 703 62 Örebro, 09:00 (Swedish)
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Available from: 2014-02-04 Created: 2014-02-04 Last updated: 2017-10-17Bibliographically approved

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Demirel, IsakVumma, RaviPersson, Katarina

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