The role of endothelial cell apoptosis in the effect of etanercept in psoriasis.
BACKGROUND
Psoriasis is a chronic inflammatory skin disease associated with abnormal vascular expansion in the papillary dermis. Tumour necrosis factor (TNF)-α is a proinflammatory cytokine that can induce antiapoptotic proteins and endothelial cell activation factors in psoriasis.


OBJECTIVE
The present study investigated the effect of the anti-TNF-α agent etanercept on the expression of endothelial nuclear factor-κB (NF-κB), angiogenic vascular endothelial growth factor (VEGF), endothelial cell marker CD31, antiangiogenic factor thrombospondin-1 (TSP-1), and antiapoptotic factors Bcl-2 and Bcl-xL in psoriasis.


METHODS
Sixteen patients with moderate-to-severe psoriasis were included in the study and treated with etanercept 50 mg twice weekly subcutaneously for 12 weeks. Biopsies of lesional skin (baseline, weeks 3, 6 and 10) were obtained and immunohistochemically stained with antibodies for CD31, VEGF, TSP-1, NF-κB, Bcl-2 and Bcl-xL. Double immunofluorescence staining for VEGF and CD31 was evaluated with confocal laser microscopy. The terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling (TUNEL) assay was applied for apoptosis detection.


RESULTS
Etanercept caused a statistically significant time-dependent reduction in the number of dermal blood vessels, the number of CD31+ cells and VEGF in psoriatic lesions, with induction of endothelial cell apoptosis and statistically significant upregulation of TSP-1 in psoriatic vessels. Immunohistochemical analysis showed significant reduction of NF-κB, Bcl-2 and Bcl-xL expression in endothelial cells during treatment. These changes were accompanied by a marked clinical response.


CONCLUSIONS
The present findings suggest that treatment with etanercept induces apoptosis, reduces apoptosis-inhibiting factors in psoriatic endothelial cells, and decreases angiogenesis in psoriatic skin.
Avramidis
G
G
Department of Dermatology, University General Hospital of Heraklion, GR-71110 Heraklion-Crete, Greece. avramidis@edu.med.uoc.gr
Krüger-Krasagakis
S
S
Krasagakis
K
K
Fragiadaki
I
I
Kokolakis
G
G
Tosca
A
A
D000328:Adult; D017209:Apoptosis / Q000187:drug effects*; D001706:Biopsy; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D000068800:Etanercept; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology*; D007150:Immunohistochemistry; D007155:Immunologic Factors / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011565:Psoriasis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018124:Receptors, Tumor Necrosis Factor; D019700:Thrombospondin 1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
C494811:BCL2L1 protein, human; D007074:Immunoglobulin G; D007155:Immunologic Factors; D016328:NF-kappa B; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor; D019700:Thrombospondin 1; D042461:Vascular Endothelial Growth Factor A; D051020:bcl-X Protein; D000068800:Etanercept