The mechanisms of action of marketed TNF-blocking drugs in lesional tissues are still incompletely understood. Because psoriasis plaques are accessible to repeat biopsy, the effect of TNF/lymphotoxin blockade with etanercept (soluble TNFR) was studied in ten psoriasis patients treated for 6 months. Histological response, inflammatory gene expression, and cellular infiltration in psoriasis plaques were evaluated. There was a rapid and complete reduction of IL-1 and IL-8 (immediate/early genes), followed by progressive reductions in many other inflammation-related genes, and finally somewhat slower reductions in infiltrating myeloid cells (CD11c+ cells) and T lymphocytes. The observed decreases in IL-8, IFN-γ-inducible protein-10 (CXCL10), and MIP-3α (CCL20) mRNA expression may account for decreased infiltration of neutrophils, T cells, and dendritic cells (DCs), respectively. DCs may be less activated with therapy, as suggested by decreased IL-23 mRNA and inducible NO synthase mRNA and protein. Decreases in T cell-inflammatory gene expression (IFN-γ, STAT-1, granzyme B) and T cell numbers may be due to a reduction in DC-mediated T cell activation. Thus, etanercept-induced TNF/lymphotoxin blockade may break the potentially self-sustaining cycle of DC activation and maturation, subsequent T cell activation, and cytokine, growth factor, and chemokine production by multiple cell types including lymphocytes, neutrophils, DCs, and keratinocytes. This results in reversal of the epidermal hyperplasia and cutaneous inflammation characteristic of psoriatic plaques.

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.