Background Antitumour necrosis factor (anti-TNF)-α therapy has made a significant impact on the treatment of psoriasis. Despite these agents being designed to neutralize TNF-α activity, their mechanism of action in the resolution of psoriasis remains unclear. Objectives To understand better the mechanism of action of etanercept by examining very early changes in the lesional skin of patients with psoriasis responding to etanercept. Methods Twenty patients with chronic plaque psoriasis were enrolled and received etanercept 50 mg twice weekly. Skin biopsies were obtained before treatment and on days 1, 3, 7 and 14 post-treatment. Skin mRNA expression was analysed by quantitative reverse-transcription polymerase chain reaction and microarray; cytokine and phosphoprotein levels were assessed using multiplexed bead arrays. Results In etanercept responders, we observed no significant changes in interleukin (IL)-17A, IL-22 or interferon-γ mRNA or protein in the first week of treatment; however, there was a 2·5-fold downregulation of IL-17 receptor C (IL-17RC) mRNA (P < 0·05) after day 1, accompanied by decreased extracellular signal-regulated kinase-1/2 phosphorylation. Transcriptional analysis revealed that genes suppressed by etanercept significantly overlapped with IL-17A-induced genes, and a marked overlap was also observed between the genes suppressed by etanercept and by the anti-IL-17A agent ixekizumab. Finally we show that TNF-α enhances the expression of IL-17RC, and short hairpin RNA inhibition of IL-17R expression abrogates synergistic gene induction by TNF and IL-17A. Conclusions These results suggest that the early responses of psoriasis plaques to etanercept may be due to decreased tissue responsiveness to IL-17A due to suppressed IL-17RC expression in keratinocytes, blunting the strong synergy between TNF-α and IL-17, which contributes to the maintenance of psoriasis lesions. What's already known about this topic? Tumour necrosis factor (TNF)-α inhibitors are effective for the treatment of psoriasis, yet their mode of action appears to involve more than just inhibition of TNF-α responses. What does this study add? This study provides evidence that the early responses of psoriasis plaques to etanercept may be due to diminished tissue responsiveness to interleukin (IL)-17A as a result of the decreased expression of IL-17 receptor C. This effect blunts responses to T helper 17 cytokines and breaks a potentially self-sustaining cycle that contributes to the maintenance of psoriasis lesions.
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