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The alpha 7 nicotinic receptor agonist PHA-543613 hydrochloride inhibits Porphyromonas gingivalis-induced expression of interleukin-8 by oral keratinocytes

Lookup NU author(s): Dr Christopher NileORCiD


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Objective: The alpha 7 nicotinic receptor (α7nAChR) is expressed by oral keratinocytes. α7nAChR activation mediates anti-inflammatory responses. The objective of this study was to determine if α7nAChR activation inhibited pathogen-induced interleukin-8 (IL-8) expression by oral keratinocytes. Materials and methods: Periodontal tissue expression of α7nAChR was determined by real-time PCR. OKF6/TERT-2 oral keratinocytes were exposed to Porphyromonas gingivalis in the presence and absence of a α7nAChR agonist (PHA-543613 hydrochloride) alone or after pre-exposure to a specific α7nAChR antagonist (α-bungarotoxin). Interleukin-8 (IL-8) expression was measured by ELISA and real-time PCR. Phosphorylation of the NF-κB p65 subunit was determined using an NF-κB p65 profiler assay and STAT-3 activation by STAT-3 in-cell ELISA. The release of ACh from oral keratinocytes in response to P. gingivalis lipopolysaccharide was determined using a GeneBLAzer M3 CHO-K1-bla cell reporter assay. Results: Expression of α7nAChR mRNA was elevated in diseased periodontal tissue. PHA-543613 hydrochloride inhibited P. gingivalis-induced expression of IL-8 at the transcriptional level. This effect was abolished when cells were pre-exposed to a specific α7nAChR antagonist, α-bungarotoxin. PHA-543613 hydrochloride downregulated NF-κB signalling through reduced phosphorylation of the NF-κB p65-subunit. In addition, PHA-543613 hydrochloride promoted STAT-3 signalling by maintenance of phosphorylation. Furthermore, oral keratinocytes upregulated ACh release in response to P. gingivalis lipopolysaccharide. Conclusion: These data suggest that α7nAChR plays a role in regulating the innate immune responses of oral keratinocytes. © 2014 The Author(s).

Publication metadata

Author(s): Macpherson A, Zoheir N, Awang RA, Culshaw S, Ramage G, Lappin DF, Nile CJ

Publication type: Article

Publication status: Published

Journal: Inflammation Research

Year: 2014

Volume: 63

Issue: 7

Pages: 557-568

Print publication date: 01/07/2014

Online publication date: 08/03/2014

Acceptance date: 19/02/2014

ISSN (print): 1023-3830

ISSN (electronic): 1420-908X

Publisher: Birkhauser Verlag AG


DOI: 10.1007/s00011-014-0725-5

PubMed id: 24609617


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