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Differential Expression of Phosphorylated NF-κB/RelA in Normal and Psoriatic Epidermis and Downregulation of NF-κB in Response to Treatment with Etanercept
- Source :
- Journal of Investigative Dermatology. 124(6):1275-1283
- Publication Year :
- 2005
- Publisher :
- Elsevier BV, 2005.
-
Abstract
- 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.
- Subjects :
- Adult
Recombinant Fusion Proteins
Transcription Factor RelA
Down-Regulation
keratinocyte
Dermatology
Biochemistry
NF-κB
Receptors, Tumor Necrosis Factor
Etanercept
Proinflammatory cytokine
Psoriatic arthritis
Downregulation and upregulation
Psoriasis
medicine
Humans
Single-Blind Method
Phosphorylation
Molecular Biology
Cell Proliferation
Skin
business.industry
Anti-Inflammatory Agents, Non-Steroidal
apoptosis
NF-kappa B
Cell Differentiation
Cell Biology
Middle Aged
medicine.disease
medicine.anatomical_structure
Immunoglobulin G
Immunology
Cancer research
Tumor necrosis factor alpha
Epidermis
business
Keratinocyte
medicine.drug
Subjects
Details
- ISSN :
- 0022202X
- Volume :
- 124
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Journal of Investigative Dermatology
- Accession number :
- edsair.doi.dedup.....7af83a5dc0205c00bb1caf192b9305c4
- Full Text :
- https://doi.org/10.1111/j.0022-202x.2005.23735.x