title: 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.
abstract: OBJECTIVE
  To investigate Toll-like receptor activation in human skin using tape stripping and imiquimod cream challenges in healthy volunteers.
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Immunoinflammation TA, GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK, marion.c.dickson@gsk.com.
authors.forename: Marion C
authors.initials: MC
authors.lastname: Dickson
authors.forename: Valerie J
authors.initials: VJ
authors.lastname: Ludbrook
authors.forename: Hayley C
authors.initials: HC
authors.lastname: Perry
authors.forename: Paul A
authors.initials: PA
authors.lastname: Wilson
authors.forename: Sam J
authors.initials: SJ
authors.lastname: Garthside
authors.forename: Michael H
authors.initials: MH
authors.lastname: Binks
mesh_terms: D015088:2',5'-Oligoadenylate Synthetase / Q000235:genetics / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000634:Aminoquinolines / Q000008:administration & dosage / Q000009:adverse effects; D001706:Biopsy; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D003872:Dermatitis / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D000077271:Imiquimod; D007370:Interferon Type I / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D008957:Models, Genetic; D011499:Protein Processing, Post-Translational / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D012867:Skin / Q000378:metabolism / Q000473:pathology; D063465:Skin Cream / Q000009:adverse effects; D053832:Surgical Tape / Q000009:adverse effects; D055815:Young Adult
chemical_list: D000634:Aminoquinolines; C114753:CXCL10 protein, human; D054357:Chemokine CXCL10; D007370:Interferon Type I; D035683:MicroRNAs; C475085:OAS1 protein, human; D015088:2',5'-Oligoadenylate Synthetase; D000077271:Imiquimod