The impact of simvastatin on pulmonary effectors of Pseudomonas aeruginosa infection

Emma Hennessy; Julie O'Callaghan; Marlies J Mooij; Claire Legendre; Olga Camacho-Vanegas; Sandra C Camacho; Claire Adams; John A Martignetti; Fergal O'Gara

doi:10.1371/journal.pone.0102200

The impact of simvastatin on pulmonary effectors of Pseudomonas aeruginosa infection

PLoS One. 2014 Jul 10;9(7):e102200. doi: 10.1371/journal.pone.0102200. eCollection 2014.

Authors

Emma Hennessy¹, Julie O'Callaghan¹, Marlies J Mooij¹, Claire Legendre¹, Olga Camacho-Vanegas², Sandra C Camacho², Claire Adams¹, John A Martignetti², Fergal O'Gara³

Affiliations

¹ BIOMERIT Research Centre, School of Microbiology, National University of Ireland, Cork, Ireland.
² Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
³ BIOMERIT Research Centre, School of Microbiology, National University of Ireland, Cork, Ireland; School of Biomedical Sciences, Curtin University, Perth, WA, Australia.

Abstract

The statin family of cholesterol-lowering drugs is known to have pleiotropic properties which include anti-inflammatory and immunomodulatory effects. Statins exert their pleiotropic effects by altering expression of human immune regulators including pro-inflammatory cytokines. Previously we found that statins modulate virulence phenotypes of the human pathogen Pseudomonas aeruginosa, and sought to investigate if simvastatin could alter the host response to this organism in lung epithelial cells. Simvastatin increased the expression of the P. aeruginosa target genes KLF2, KLF6, IL-8 and CCL20. Furthermore, both simvastatin and P. aeruginosa induced alternative splicing of KLF6. The novel effect of simvastatin on wtKLF6 expression was found to be responsible for induction of the KLF6 regulated genes CCL20 and iNOS. Simvastatin also increased the adhesion of P. aeruginosa to host cells, without altering invasion or cytotoxicity. This study demonstrated that simvastatin had several novel effects on the pulmonary cellular immune response.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alternative Splicing / drug effects
Cell Line
Chemokine CCL20 / biosynthesis
Gene Expression Regulation / drug effects*
Humans
Immunity, Cellular / drug effects
Interleukin-8 / biosynthesis
Kruppel-Like Factor 6
Kruppel-Like Transcription Factors / biosynthesis
Lung / drug effects
Lung / immunology
Lung / pathology
Proto-Oncogene Proteins / biosynthesis
Pseudomonas Infections / drug therapy*
Pseudomonas Infections / genetics
Pseudomonas Infections / pathology
Pseudomonas aeruginosa / drug effects*
Pseudomonas aeruginosa / pathogenicity
Simvastatin / administration & dosage*

Substances

CCL20 protein, human
Chemokine CCL20
Interleukin-8
KLF2 protein, human
KLF6 protein, human
Kruppel-Like Factor 6
Kruppel-Like Transcription Factors
Proto-Oncogene Proteins
Simvastatin

Grants and funding

This research was supported in part by grants awarded by the European Commission (http://ec.europa.eu/index_en.htm)(FP7-PEOPLE-2013-ITN, 607786; FP7-KBBE-2012-6, CP-TP-312184; FP7-KBBE-2012-6, 311975; OCEAN 2011-2, 287589; Marie Curie 256596), Science Foundation Ireland (www.sfi.ie)(SSPC-2; 07/IN.1/B948; 12/TIDA/B2411; 12/TIDA/B2405; 09/RFP/BMT2350), the Department of Agriculture and Food (www.agriculture.gov.ie/) (FIRM/RSF/CoFoRD; FIRM 08/RDC/629), the Irish Research Council for Science, Engineering and Technology (www.research.ie/) (PD/2011/2414; RS/2010/2413), the Health Research Board (www.hrb.ie)(RP/2006/271; RP/2007/290; HRA/2009/146), the Environmental Protection Agency (www.epa.ie) (EPA2006-PhD-S-21; EPA2008-PhD-S-2), the Marine Institute (https://www.marine.ie) (Beaufort award C2CRA 2007/082) Teagasc (www.teagasc.ie) (Walsh Fellowship 2013), the Higher Education Authority of Ireland (www.hea.ie)(PRTLI4) and the Society For General Microbiology President's Fund for Research Visits (www.sgm.ac.uk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.