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Markham, T,Mathews, C,Rogers, S,Mullan, R,Bresnihan, B,FitzGerald, O,Veale, DJ,Fearon, U
British Journal Of Dermatology
Downregulation of the inhibitor of apoptosis protein survivin in keratinocytes and endothelial cells in psoriasis skin following infliximab therapy
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angiogenesis infliximab keratinocytes psoriasis survivin TUMOR-NECROSIS-FACTOR EXPRESSION PROLIFERATION LYMPHOCYTES BLOCKADE
Background Survivin, an inhibitor of apoptosis protein (IAP), has been implicated in endothelial cell stability, through inhibition of apoptosis and in cell proliferation.Objectives To evaluate the effect of antitumour necrosis factor (TNF)-alpha therapy on survivin expression in psoriasis skin at 0, 2 and 12 weeks after infliximab therapy.Methods Skin biopsies were obtained from 16 patients; I I also had arthritis with active skin/joint disease. Clinical scores [Psoriasis Area and Severity Index (PASI), involved body surface area (BSA), Disease Activity Score (DAS28) and Health Assessment Questionnaire] were recorded. Inflammatory infiltration and survivin protein expression were examined and graded by immunohistochemical staining, and mRNA levels were determined by real-time polymerase chain reaction.Results Survivin mRNA and protein were demonstrated in all baseline lesional biopsies. Survivin mRNA and protein expression was significantly greater in lesional. compared with nonlesional baseline skin (P < 0.05). Differential cellular localization of survivin was demonstrated with cytoplasmic survivin protein expression localized to the perivascular/endothelial regions and strong nuclear staining localized in the basal layer of the epidermis. lnfliximab produced a dramatic clinical response in skin and joints (P < 0.05), paralleled by significant reduction in the inflammatory infiltrate and survivin protein expression (P < 0.05) which was reflected at the mRNA level where expression was significantly reduced by week 12 (P < 0.01). Survivin protein levels before and after treatment significantly correlated with PASI (r = 0.478, P < 0.05) and BSA scores (r = 0.528, P < 0.024). PASI strongly correlated with BSA (r = 0.949, P < 0.0001) and DAS28 (r = 0.717, P < 0.002) scores.Conclusions Survivin correlates with disease activity in patients with psoriasis and is significantly downregulated following anti-TNF-alpha treatment. Understanding the role of IAPs in cell survival/antiapoptosis and proliferation mechanisms may provide important insights into downstream therapeutic targeting in inflammation.
DOI 10.1111/j.1365-2133.2006.07522.x
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