Clinical Research Center, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA

Correspondence: Paul F. Lizzul, Clinical Research Center, UMDNJ-Robert Wood Johnson Medical School, 51 French St., New Brunswick, NJ 08901-0019, USA. Email: lizzulpa@umdnj.edu

Received 18 October 2004; Revised 11 January 2005; Accepted 25 January 2005; Published online 3 June 2005.

Abstract

Etanercept, a recombinant human tumor necrosis factor (TNF) receptor fusion protein, is FDA approved for psoriasis and psoriatic arthritis. TNF increases the synthesis of proinflammatory cytokines and leads to the activation of multiple signaling pathways, including nuclear factor kappa B (NF-B). The Rel/NF-B 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-B/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-B in the normal epidermis, whereas a basal level of constitutive active phosphorylated NF-B/RelA was present in uninvolved epidermis from psoriasis patients. There was also significant upregulation of active phosphorylated NF-B/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-B/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-B plays a significant role in the pathogenesis of psoriasis and that a potential mechanism of action for TNF-targeting agents is downregulation of NF-B transcriptional activity.