Journal
BMC GENOMICS
Volume 14, Issue -, Pages -Publisher
BMC
DOI: 10.1186/1471-2164-14-527
Keywords
AP-1; Etanercept; IL-17; IL-20; Inflammation; Keratinocyte; Microarray; TNF; T-cell; Transcription factor
Funding
- NIH [K08 AR060802, R01 AR054966]
- Babcock Endowment Fund
- Dermatology Foundation
- American Skin Association
- A. Alfred Taubman Medical Research Institute Kenneth and Frances Eisenberg Emerging Scholar Award
- Ann Arbor VA Hospital
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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-gamma-strong signature, with increased expression of genes induced by IFN-gamma 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.
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