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Background: Etanercept is a tumor necrosis factor-alpha binding fusion protein that demonstrates efficacy in the treatment of psoriasis, which is accompanied by decreased plaque infiltration of T cells and myeloid dendritic cells. We hypothesized that etanercept decreases inflammatory cell infiltration by inducing apoptosis., Objective: We sought to investigate the effect of etanercept on circulating and plaque leukocyte apoptosis in psoriasis., Methods: Blood and plaque specimens were obtained from 10 patients with psoriasis treated with etanercept (25 mg subcutaneously twice weekly) for 24 weeks. Apoptosis was determined in tissue samples using immunohistochemistry and flow cytometry., Results: Etanercept selectively induced apoptosis in dermal dendritic cells in plaques of responding patients at 1 month, before most of the clinical and histologic response was achieved. No apoptosis was detected in plaque or circulating T cells or in circulating monocytes., Limitations: Addition of multiple time points earlier than 1 month would be valuable to establish the time point of maximum induction in cell apoptosis., Conclusion: Etanercept selectively induces apoptosis of pathogenic dermal dendritic cells in responding patients early in the course of treatment.

Infliximab demonstrates high efficacy in treating psoriasis in a high proportion of patients. In this report we demonstrate induction of plaque (T cells, dendritic cells) and peripheral blood (T cells, monocytes) leukocyte apoptosis following a single infliximab infusion in a psoriasis patient.

Summary: Tumor suppressor p53 plays a central role in tumor prevention. p53 protein levels and activity are under a tight and complex regulation in cells to maintain the proper function of p53. MicroRNAs play a key role in the regulation of gene expression. Here we report the regulation of p53 through miR-504. miR-504 acts as a negative regulator of human p53 through its direct binding to two sites in the p53 3′ untranslated region. Overexpression of miR-504 decreases p53 protein levels and functions in cells, including p53 transcriptional activity, p53-mediated apoptosis, and cell-cycle arrest in response to stress, and furthermore promotes tumorigenecity of cells in vivo. These results demonstrate the direct negative regulation of p53 by miR-504 as a mechanism for p53 regulation in cells, which highlights the importance of microRNAs in tumorigenesis. [Copyright &y& Elsevier]

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