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A model of skin inflammation in humans leads to a rapid and reproducible increase in the interferon response signature: a potential translational model for drug development

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Abstract

Objectives

To investigate Toll-like receptor activation in human skin using tape stripping and imiquimod cream challenges in healthy volunteers.

Subjects, treatment and methods

Seventeen male Caucasian subjects underwent a baseline biopsy on their lower back prior to two tape stripping procedures 7 days apart. Subjects were then treated with 5 % imiquimod for 2 and 4 days on separate sites in the same area. Further biopsies were taken 22–24 h after each challenge and mRNA and microRNA extracted and expression values analysed using robust statistical and pathway analysis methods.

Results

Fifteen of the 17 subjects completed the study according to protocol. No adverse events were associated with the procedures. A significant change (p < 0.05, fold change >1.5 or <−1.5) in mRNA expression of 7,996 genes was evident in biopsies taken at both time points post tape stripping, compared to baseline biopsy expression values. The induction of mRNAs involved in various pathways including adhesion and migration was evident. mRNA markers representing inflammatory cells [e.g., CD14, CD3E (p < 0.0001)] and mRNAs encoding genes regulated by type 1 interferon (IFN) [e.g., MX1, OAS1and CXCL10 (p < 0.0001)] were significantly up-regulated. IFNα and CXCL10 proteins were detectable in exudates released 1 and 4 h post tape stripping. A putative signalling network associating these transcripts and six microRNAs (hsa-miR, -31, -132, -155, 548c, 548n and 574) was identified using a meta-regulation network model. microRNAs not previously associated with IFN signalling have been identified. In contrast, only 223 known transcripts were significantly changed after imiquimod treatment, including CXCL10, and OAS1.

Conclusion

Results suggest that IFN signalling is important in these translational models and novel miRNA may be new targets in the treatment of IFN associated skin disease.

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Acknowledgments

The authors would gratefully like to acknowledge Anita Kapur for her operational leadership throughout the study. This study was funded by GlaxoSmithKline.

Conflict of interest

All authors were employees and share holders in GlaxoSmithKline at the time the work reported in this manuscript was performed. All authors have read the journal’s authorship agreement and policy on disclosure of potential conflicts of interest.

Ethical standards

The study reference number is EMI113437 and was approved by the IntegReview Ethical Review Board Austin, Texas on December 1st 2009. As this was a non interventional study a clinical trial application was not required at the time of study initiation. The study was conducted in accordance with all applicable regulatory requirements. The study was conducted in accordance with “good clinical practice” (GCP), all applicable subject privacy requirements, and the guiding principles of the 2008 Declaration of Helsinki. This includes, but is not limited to, the following: (1) IRB/IEC review and favourable opinion/approval to conduct the study and of any subsequent relevant amended documents, (2) written informed consent (and any amendments) to be obtained for each subject before participation in the study, (3) investigator reporting requirements (e.g., reporting of AEs/SAEs/protocol deviations to IRB/IEC).

Author information

Author notes

  1. Michael H. Binks

    Present address: Rare Disease Clinical Research, Pfizer, Cambridge, MA, USA

Authors and Affiliations

  1. Immunoinflammation TA, GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK

    Marion C. Dickson, Valerie J. Ludbrook & Michael H. Binks

  2. QSCI Clinical Statistics, GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK

    Hayley C. Perry

  3. QSCI Computational Biology, GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK

    Paul A. Wilson

  4. CPSSO Projects Clinical Platforms and Sciences, GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK

    Sam J. Garthside

Authors
  1. Marion C. Dickson
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  2. Valerie J. Ludbrook
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  3. Hayley C. Perry
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  4. Paul A. Wilson
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  5. Sam J. Garthside
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Corresponding author

Correspondence to Marion C. Dickson.

Additional information

Responsible Editor: Yoshiya Tanaka.

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Dickson, M.C., Ludbrook, V.J., Perry, H.C. et al. A model of skin inflammation in humans leads to a rapid and reproducible increase in the interferon response signature: a potential translational model for drug development. Inflamm. Res. 64, 171–183 (2015). https://doi.org/10.1007/s00011-015-0795-z

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  • DOI: https://doi.org/10.1007/s00011-015-0795-z

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