title: Dissecting the psoriasis transcriptome: inflammatory- and cytokine-driven gene expression in lesions from 163 patients.
abstract: BACKGROUND
  Psoriasis lesions are characterized by large-scale shifts in gene expression. Mechanisms that underlie differentially expressed genes (DEGs), however, are not completely understood. We analyzed existing datasets to evaluate genome-wide expression in lesions from 163 psoriasis patients. Our aims were to identify mechanisms that drive differential expression and to characterize heterogeneity among lesions in this large sample.
  
  
  RESULTS
  We identified 1233 psoriasis-increased DEGs and 977 psoriasis-decreased DEGs. Increased DEGs were attributed to keratinocyte activity (56%) and infiltration of lesions by T-cells (14%) and macrophages (11%). Decreased DEGs, in contrast, were associated with adipose tissue (63%), epidermis (14%) and dermis (4%). KC/epidermis DEGs were enriched for genes induced by IL-1, IL-17A and IL-20 family cytokines, and were also disproportionately associated with AP-1 binding sites. Among all patients, 50% exhibited a heightened inflammatory signature, with increased expression of genes expressed by T-cells, monocytes and dendritic cells. 66% of patients displayed an IFN-γ-strong signature, with increased expression of genes induced by IFN-γ in addition to several other cytokines (e.g., IL-1, IL-17A and TNF). We show that such differences in gene expression can be used to differentiate between etanercept responders and non-responders.
  
  
  CONCLUSIONS
  Psoriasis DEGs are partly explained by shifts in the cellular composition of psoriasis lesions. Epidermal DEGs, however, may be driven by the activity of AP-1 and cellular responses to IL-1, IL-17A and IL-20 family cytokines. Among patients, we uncovered a range of inflammatory- and cytokine-associated gene expression patterns. Such patterns may provide biomarkers for predicting individual responses to biologic therapy.
authors.affiliation: Department of Dermatology, University of Michigan School of Medicine, Ann Arbor, MI 48109-2200, USA. wswindel@umich.edu
authors.forename: William R
authors.initials: WR
authors.lastname: Swindell
authors.forename: Andrew
authors.initials: A
authors.lastname: Johnston
authors.forename: John J
authors.initials: JJ
authors.lastname: Voorhees
authors.forename: James T
authors.initials: JT
authors.lastname: Elder
authors.forename: Johann E
authors.initials: JE
authors.lastname: Gudjonsson
mesh_terms: D001665:Binding Sites; D016207:Cytokines / Q000378:metabolism*; D020405:Dermis / Q000187:drug effects / Q000378:metabolism; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism; D000068800:Etanercept; D020869:Gene Expression Profiling; D023281:Genomics; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology / Q000627:therapeutic use; D007249:Inflammation / Q000235:genetics; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D009928:Organ Specificity; D046988:Proteasome Endopeptidase Complex / Q000276:immunology; D011565:Psoriasis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D012867:Skin / Q000473:pathology; D050151:Subcutaneous Fat / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016207:Cytokines; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D046988:Proteasome Endopeptidase Complex; D000068800:Etanercept
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