Preferential inhibition of the mRNA expression of p38 mitogen-activated protein kinase regulated cytokines in psoriatic skin by anti-TNFα therapy
Preferential inhibition of the mRNA expression of p38 mitogen-activated protein kinase regulated cytokines in psoriatic skin by anti-TNFα therapy
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DOI：
10.1111/j.1365-2133.2010.10036.x
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发表时间：
2010-12-01
影响因子：
10.3
通讯作者：
Kragballe, K.
中科院分区：
文献类型：
--
作者：
Johansen, C.;Vinter, H.;Kragballe, K.
背景抗TNF α治疗重度银屑病已得到公认;然而，其在疾病消退中的作用机制尚不完全清楚。p38丝裂原活化蛋白激酶（MAPK）是一种激酶，已知发挥关键作用的发病机制psorias.ObjectiveTo阐明阿达木单抗，人单克隆抗TNF α抗体，对白细胞介素在银屑病skin.Patients和方法的表达的早期影响，从银屑病患者的活检组织进行检查之前和之后开始的阿达木单抗治疗。定量聚合酶链反应检测细胞因子mRNA的表达。结果阿达木单抗治疗4 d后，银屑病皮损中IL-1 β、IL-8、IL-17 C和IL-20的mRNA水平明显降低，IL-1 β、IL-8、IL-17 C和IL-20的mRNA水平明显降低，IL-17 A和IL-17 C的mRNA水平明显降低，IL-17 A和IL-17 C的mRNA水平明显降低，IL-17 A和IL-17 C的mRNA水平明显降低。即在可检测到临床和组织学改善之前。Th17衍生的细胞因子IL-17 A、IL-17 F和IL-22以及树突状细胞产物IL-23/IL-12（p40）的mRNA表达直到治疗开始后2周才显著降低，而IL-23（p19）和Th1细胞因子IFN-γ和IL-2的mRNA表达在疾病消退后期降低。已知IL-1 β、IL-8和IL-20均受p38 MAPK调节。IL-17 C由培养的人角质形成细胞产生，并且这种产生也由p38 MAPK依赖性机制介导。此外，阿达木单抗的早期影响包括p38 MAPK的磷酸化，但不是STAT3 phosphorylation.Conclusions这项研究表明，抗TNF α治疗银屑病的作用的一个重要机制是减少p38 MAPK磷酸化和随后的p38 MAPK调控基因的表达减少。
Background Anti-TNF alpha therapies are well established for severe psoriasis; however, their mechanism of action in disease resolution is not fully understood. p38 mitogen-activated protein kinase (MAPK) is a kinase known to play a key role in the pathogenesis of psoriasis.Objectives To elucidate the early effects of adalimumab, a human monoclonal anti-TNF alpha antibody, on the expression of interleukins in psoriatic skin.Patients and methods Biopsies from patients with psoriasis were examined before and after the start of adalimumab therapy. mRNA expression of cytokines were measured with quantitative polymerase chain reaction. p38 MAPK and signal transducer and activator of transcription 3 (STAT3) were analysed by Western blotting and immunofluorescence analyses, and IL-17A and IL-17C were examined with immunohistochemistry.Results The increased mRNA level of IL-1 beta, IL-8, IL-17C and IL-20 in lesional psoriatic skin was already significantly reduced 4 days after the start of adalimumab treatment, i.e. before clinical and histological improvement was detectable. The mRNA expression of the Th17-derived cytokines IL-17A, IL-17F and IL-22 as well as the dendritic cell product IL-23/IL-12 (p40) were not significantly reduced until 2 weeks after the start of treatment, whereas the mRNA expression of IL-23 (p19) and the Th1 cytokines IFN-gamma and IL-2 were reduced late in disease resolution. IL-1 beta, IL-8 and IL-20 are all known to be regulated by p38 MAPK. IL-17C was produced by cultured human keratinocytes and this production was also mediated by a p38 MAPK dependent mechanism. Moreover, the early effects of adalimumab included the phosphorylation of p38 MAPK, but not STAT3 phosphorylation.Conclusions This study indicates that an important mechanism of action of anti-TNF alpha therapy in psoriasis is a reduction in p38 MAPK phosphorylation and a subsequent decrease in the expression of p38 MAPK regulated genes.