Departments of Dermatology and Histopathology, University Hospital of Heraklion, University of Crete, 71110 Heraklion, Crete, Greece.
Br J Dermatol. 2012 Mar;166(3):491-7. doi: 10.1111/j.1365-2133.2011.10689.x. Epub 2012 Jan 9.
Psoriasis and psoriatic arthritis are treated very efficaciously with infliximab, a chimaeric human-murine antitumour necrosis factor (TNF)-α antibody. As we reported earlier, infliximab, besides its anti-inflammatory properties, induces a caspase-independent programmed cell death of psoriatic keratinocytes.
To elucidate this finding further, we investigated the epidermal expression of proteins involved in the mitochondria-dependent (intrinsic) pathway of cell death.
Quantification of proteins with pro- (p53, AIF, Bax) and anti-apoptotic functions (Bcl-2, Bcl-XL) and of NF-κB was performed by means of immunohistochemistry and digital image analysis of the staining of nonlesional skin and lesional psoriatic skin from patients treated with infliximab at weeks 0, 2 and 6.
Serial biopsies from psoriatic plaques of samples taken at days 0, 5, 14 and 21 of therapy demonstrated a significant downregulation of anti-apoptotic proteins Bcl-2, Bcl-XL and NF-κB during treatment and, in parallel, a significant upregulation of pro-apoptotic proteins p53, Bax and AIF. These differences in expression correlated with decreases in epidermal thickness and clinical outcome (Psoriasis Area and Severity Index). At day 21, expression levels of apoptosis-related proteins in lesional skin approximated those found in nonlesional skin.
Our data therefore suggest that TNF-targeting agents may induce the regression of psoriasis at least in part by normalizing the expression of apoptosis-related proteins in lesional keratinocytes.
英夫利昔单抗是一种嵌合人鼠抗肿瘤坏死因子（TNF）-α 抗体，对银屑病和银屑病关节炎的治疗非常有效。正如我们之前报道的，除了具有抗炎特性外，英夫利昔单抗还诱导银屑病角质形成细胞发生 caspase 非依赖性程序性细胞死亡。
为了进一步阐明这一发现，我们研究了参与细胞死亡线粒体依赖性（内在）途径的蛋白在表皮中的表达。
采用免疫组化和染色的数字图像分析方法，检测非病变皮肤和病变银屑病皮肤中与促凋亡（p53、AIF、Bax）和抗凋亡功能（Bcl-2、Bcl-XL）以及 NF-κB 相关蛋白的表达，这些标本取自接受英夫利昔单抗治疗的患者，时间点分别为 0、2 和 6 周。
在治疗的第 0、5、14 和 21 天，对银屑病斑块进行连续活检，结果显示，在治疗过程中，抗凋亡蛋白 Bcl-2、Bcl-XL 和 NF-κB 的表达显著下调，同时促凋亡蛋白 p53、Bax 和 AIF 的表达显著上调。这些表达差异与表皮厚度的减少和临床疗效（银屑病面积和严重程度指数）相关。在第 21 天，病变皮肤中凋亡相关蛋白的表达水平接近非病变皮肤。
因此，我们的数据表明，TNF 靶向药物可能通过使病变角质形成细胞中凋亡相关蛋白的表达正常化，至少部分地诱导银屑病的消退。
