Integrative Responses to IL-17 and TNF-α in Human Keratinocytes Account for Key Inflammatory Pathogenic Circuits in Psoriasis
Integrative Responses to IL-17 and TNF-α in Human Keratinocytes Account for Key Inflammatory Pathogenic Circuits in Psoriasis
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DOI：
10.1038/jid.2010.340
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发表时间：
2011-03-01
影响因子：
6.5
通讯作者：
Krueger, James G.
中科院分区：
文献类型：
--
作者：
Chiricozzi, Andrea;Guttman-Yassky, Emma;Krueger, James G.
银屑病是一种由肿瘤坏死因子（TNF）-α和特化T细胞群分泌的细胞因子介导的复杂炎症性疾病。例如，在一个实施例中，IL-17、IL-22和IFN-γ。先天性和适应性免疫细胞因子调节银屑病炎症的机制尚不完全清楚。我们试图研究TNF-α和IL-17对角质形成细胞（KC）基因谱的影响，以鉴定可能受这些细胞因子共调节的基因，并确定协同激活的基因如何与银屑病转录组相关。用IL-17或TNF-α单独或组合刺激原代KC。通过基因阵列分析评估KC反应，然后通过逆转录酶-PCR确认重要基因。我们确定了160个基因被IL-17和TNF-α协同上调，196个基因中这两种细胞因子至少具有累加效应。协同上调的基因包括银屑病皮肤中表达最高的一些基因，其中IL-17/TNF-α诱导的基因与银屑病基因特征之间存在令人印象深刻的相关性。KCs可能是银屑病致病性炎症的关键驱动因素，通过整合对TNF-α和IL-17的反应。我们的数据预测，银屑病治疗与TNF或IL-17拮抗剂将产生更大的调节的协同/加性基因集，其中包括最高度表达的基因在银屑病皮损。
Psoriasis is a complex inflammatory disease mediated by tumor necrosis factor (TNF)-alpha and cytokines secreted by specialized T-cell populations, e. g., IL-17, IL-22, and IFN-gamma. The mechanisms by which innate and adaptive immune cytokines regulate inflammation in psoriasis are not completely understood. We sought to investigate the effects of TNF-alpha and IL-17 on keratinocyte (KC) gene profile, to identify genes that might be coregulated by these cytokines and determine how synergistically activated genes relate to the psoriasis transcriptome. Primary KCs were stimulated with IL-17 or TNF-alpha alone, or in combination. KC responses were assessed by gene array analysis, followed by reverse transcriptase-PCR confirmation for significant genes. We identified 160 genes that were synergistically upregulated by IL-17 and TNF-alpha, and 196 genes in which the two cytokines had at least an additive effect. Synergistically upregulated genes included some of the highest expressed genes in psoriatic skin with an impressive correlation between IL-17/TNF-alpha-induced genes and the psoriasis gene signature. KCs may be key drivers of pathogenic inflammation in psoriasis through integrating responses to TNF-alpha and IL-17. Our data predict that psoriasis therapy with either TNF or IL-17 antagonists will produce greater modulation of the synergistic/additive gene set, which consists of the most highly expressed genes in psoriasis skin lesions.