Transcriptional regulation of the 230-kDa bullous pemphigoid antigen gene expression by interferon regulatory factor 1 and interferon regulatory factor 2 in normal human epidermal keratinocytes
Transcriptional regulation of the 230-kDa bullous pemphigoid antigen gene expression by interferon regulatory factor 1 and interferon regulatory factor 2 in normal human epidermal keratinocytes
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DOI：
10.1111/j.0906-6705.2004.00219.x
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发表时间：
2004-12-01
影响因子：
3.6
通讯作者：
Hanada, K
中科院分区：
文献类型：
--
作者：
Odanagi, M;Kikuchi, Y;Hanada, K
干扰素调节因子（IRFs）是干扰素- γ (ifn - γ)诱导的转录因子家族。最近的研究表明，角化细胞中IRF系统的失调至少在一定程度上是银屑病表皮异常增殖和分化的原因。先前，我们报道了230-kDa的大疱性类天疱疮抗原（BPAG1）基因的表达被ifn - γ转录抑制，但irf在这种抑制中的作用尚不清楚。在本研究中，我们研究了IRFs在BPAG1基因表达调控中的作用。计算机分析确定了BPAG1启动子区-135和-123之间的IRF1和IRF2一致性序列。BPAG1启动子荧光素酶报告基因质粒和IRF1、IRF2表达质粒瞬时转染研究发现，IRF1、IRF2可直接下调培养的正常人表皮角质形成细胞中BPAG1基因的转录。以BPAG1-IRF结合序列为探针的多组凝胶阻滞实验表明，IRF1和IRF2可以与BPAG1-IRF序列结合，但其他一些受ifn - γ刺激诱导且对IRF一致序列具有结合活性的蛋白则优先与BPAG1-IRF序列结合。我们的研究结果表明，ifn - γ - irf系统参与了1型辅助性t细胞炎症性皮肤疾病（如寻常型牛皮癣）中BPAG1基因的调控。
Interferon regulatory factors (IRFs) are a family of transcriptional factors induced by interferon-gamma (IFN-gamma). Recent studies have indicated that the deregulation of IRF system in keratinocytes is responsible, at least in part, for aberrant proliferation and the differentiation of the psoriatic epidermis. Previously, we reported that the expression of 230-kDa bullous pemphigoid antigen (BPAG1) gene, which is strictly restricted to basal keratinocytes, is transcriptionally suppressed by IFN-gamma, but the contribution of IRFs in such suppression is still unclear. In this study, we investigated the role of IRFs in the regulation of BPAG1 gene expression. Computer analysis identified IRF1 and IRF2 consensus sequences between -135 and -123 on BPAG1 promoter region. Transient transfection studies with BPAG1 promoter-luciferase reporter gene plasmids and IRF1 and IRF2 expression plasmids revealed that IRF1 and IRF2 directly down-regulated BPAG1 gene transcription in cultured normal human epidermal keratinocytes. Several sets of gel retardation assays with the BPAG1-IRF binding sequence as a probe indicated that IRF1 and IRF2 could bind to the BPAG1-IRF sequence, but some other protein(s), which was induced by IFN-gamma stimulation and possessed binding activity to IRF consensus sequence, showed preferential binding to the BPAG1-IRF sequence. Our results suggest that IFN-gamma-IRF system is involved in BPAG1 gene regulation in type-1 helper T-cell inflammatory skin conditions, such as psoriasis vulgaris.