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Psoriasis is a chronic inflammatory disease of the skin affecting up to 2.5% of the world's population. The scaly, erythematous plaques characteristic of this papulosquamous disorder are likely triggered and maintained by cytokines and chemokines manufactured by cells of the immune system. Overproduction of inflammatory mediators, such as tumor necrosis factor-alpha (TNF-alpha) and IFN-gamma, results in a self-sustaining inflammatory cascade, causing abnormal keratinocyte proliferation and differentiation. Therapeutic drug design targeting TNF has led to the emergence of successful biologic agents, such as etanercept, in recent years. Despite extensive clinical trials documenting efficacious clinical response to therapy, there is a paucity of data investigating the molecular mechanisms by which etanercept modulates the improvement of psoriasis. This brief review summarizes recent work investigating the in vivo actions of etanercept, including its effects on various cell types, inflammatory pathways, gene activation, nuclear factor kappa B expression, and apoptosis. The anti-inflammatory properties of etanercept reveal mechanisms by which a TNF blockade may result in the improvement of psoriasis.

Etanercept, a recombinant human tumor necrosis factor (TNF) receptor fusion protein, is FDA approved for psoriasis and psoriatic arthritis. TNFalpha increases the synthesis of proinflammatory cytokines and leads to the activation of multiple signaling pathways, including nuclear factor kappa B (NF-kappaB). The Rel/NF-kappaB transcription factors play a central role in numerous cellular processes, including the stress response and keratinocyte proliferation and differentiation. Utilizing a phosphorylation-specific antibody, we examined the expression of active nuclear NF-kappaB/RelA via immunohistochemistry in normal skin, non-lesional psoriatic skin, lesional psoriatic skin, and lesional skin from patients treated with etanercept. There was no expression of active nuclear NF-kappaB in the normal epidermis, whereas a basal level of constitutive active phosphorylated NF-kappaB/RelA was present in uninvolved epidermis from psoriasis patients. There was also significant upregulation of active phosphorylated NF-kappaB/RelA in the epidermis from psoriatic plaques. Serial biopsies from psoriasis patients treated with etanercept at 1, 3, and 6 mo demonstrated a significant downregulation of phosphorylated NF-kappaB/RelA, which correlated with decreases in epidermal thickness, restoration of normal markers of keratinocyte differentiation, and clinical outcomes. These data suggest that activation of NF-kappaB plays a significant role in the pathogenesis of psoriasis and that a potential mechanism of action for TNF-targeting agents is downregulation of NF-kappaB transcriptional activity.