Network analysis identifies a putative role for the PPAR and type 1 interferon pathways in glucocorticoid actions in asthmatics

BMC Medical Genomics

Craig E Wheelock²  Åsa M Wheelock⁴  Prescott G Woodruff³  David J Erle³  John V Fahy³  Susumu Goto¹  Diego Diez⁵ 

[1]Bioinformatics Center, Institute for Chemical Research, Kyoto University, Uji, Kyoto, 611-0011, Japan

[2]Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry II, Karolinska Institutet, Stockholm, Sweden

[3]Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA

[4]Respiratory Medicine Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden

[5]Laboratory of Bioinformatics and Genomics, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, 565-0871, Japan

关键词: Interferon pathway;    Toll-like receptor pathway;    PPAR pathway;    Network analysis;    Flovent;    Fluticasone propionate;    Glucocorticoids;    Inflammation;    Asthma;   

Others  :  1134835
DOI  :  10.1186/1755-8794-5-27

 received in 2012-02-10, accepted in 2012-06-19,  发布年份 2012

【 摘 要 】

Background

Asthma is a chronic inflammatory airway disease influenced by genetic and environmental factors that affects ~300 million people worldwide, leading to ~250,000 deaths annually. Glucocorticoids (GCs) are well-known therapeutics that are used extensively to suppress airway inflammation in asthmatics. The airway epithelium plays an important role in the initiation and modulation of the inflammatory response. While the role of GCs in disease management is well understood, few studies have examined the holistic effects on the airway epithelium.

Methods

Gene expression data were used to generate a co-transcriptional network, which was interrogated to identify modules of functionally related genes. In parallel, expression data were mapped to the human protein-protein interaction (PPI) network in order to identify modules with differentially expressed genes. A common pathways approach was applied to highlight genes and pathways functionally relevant and significantly altered following GC treatment.

Results

Co-transcriptional network analysis identified pathways involved in inflammatory processes in the epithelium of asthmatics, including the Toll-like receptor (TLR) and PPAR signaling pathways. Analysis of the PPI network identified RXRA, PPARGC1A, STAT1 and IRF9, among others genes, as differentially expressed. Common pathways analysis highlighted TLR and PPAR signaling pathways, providing a link between general inflammatory processes and the actions of GCs. Promoter analysis identified genes regulated by the glucocorticoid receptor (GCR) and PPAR pathways as well as highlighted the interferon pathway as a target of GCs.

Conclusions

Network analyses identified known genes and pathways associated with inflammatory processes in the airway epithelium of asthmatics. This workflow illustrated a hypothesis generating experimental design that integrated multiple analysis methods to produce a weight-of-evidence based approach upon which future focused studies can be designed. In this case, results suggested a mechanism whereby GCs repress TLR-mediated interferon production via upregulation of the PPAR signaling pathway. These results highlight the role of interferons in asthma and their potential as targets of future therapeutic efforts.

【 授权许可】

   
2012 Diez et al.; licensee BioMed Central Ltd.

【 图 表 】

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