IFN. Stimulates MxA Production in Human Dermal Fibroblasts via a MAPK-Dependent STAT1-Independent Mechanism
IFN. Stimulates MxA Production in Human Dermal Fibroblasts via a MAPK-Dependent STAT1-Independent Mechanism
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DOI：
10.1038/jid.2015.317
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发表时间：
2015-12-01
影响因子：
6.5
通讯作者：
Wittmann, Miriam
中科院分区：
文献类型：
--
作者：
Alase, Adewonuola A.;El-Sherbiny, Yasser M.;Wittmann, Miriam
IFN λ对于表皮防御病毒是重要的。它是由角质形成细胞产生的，并作用于角质形成细胞，而成纤维细胞以前被认为是对这种III型IFN λ无反应的。在此，我们报告的发现揭示了皮肤驻留细胞中IFN λ信号传导和功能的细胞类型特异性差异。在真皮成纤维细胞中，IFN λ诱导了一种有效的抗病毒因子粘病毒蛋白A（MxA）的表达，但不像在原代角质形成细胞中那样诱导其他IFN特征基因的表达。与其对角质形成细胞的作用相反，IFN λ不磷酸化成纤维细胞中的信号转导子和转录激活子1，而是激活有丝分裂原活化蛋白激酶（MAPK）。因此，抑制MAPK活化（p38和p42/44）阻断成纤维细胞中MxA蛋白的表达，但不阻断角质形成细胞中MxA蛋白的表达。在功能上，IFN λ抑制角质形成细胞的增殖，但不抑制成纤维细胞的增殖。此外，IFN λ上调成纤维细胞中肿瘤生长因子β 1（TGF β 1）诱导的胶原蛋白的表达。两者合计，我们的研究结果确定原代人皮肤成纤维细胞作为IFN λ的应答细胞。我们的研究表明，皮肤细胞类型特异性IFN信号，并表明，IFN λ，虽然重要的表皮抗病毒能力，也可能有一个调节作用，在真皮隔室平衡I型IFN诱导的抑制组织修复过程。
IFN lambda is important for epidermal defense against viruses. It is produced by, and acts on, keratinocytes, whereas fibroblasts were previously considered to be unresponsive to this type III IFN lambda Herein we report findings revealing cell type-specific differences in IFN lambda signaling and function in skin resident cells. In dermal fibroblasts, IFN lambda induced the expression of myxovirus protein A (MxA), a potent antiviral factor, but not other IFN signature genes as it does in primary keratinocytes. In contrast to its effect on keratinocytes, IFN lambda did not phosphorylate signal transducer and activator of transcription 1 in fibroblasts, but instead activated mitogen activated protein kinases (MAPK). Accordingly, inhibition of MAPK activation (p38 and p42/44) blocked the expression of MxA protein in fibroblasts but not in keratinocytes. Functionally, IFN lambda inhibited proliferation in keratinocytes but not in fibroblasts. Moreover, IFN lambda upregulated the expression of Tumor growth factor beta 1 (TGF beta 1)-induced collagens in fibroblasts. Taken together, our findings identify primary human dermal fibroblasts as responder cells to IFN lambda. Our study shows cutaneous cell type-specific IFN signaling and suggests that IFN lambda, although important for epidermal antiviral competence, may also have a regulatory role in the dermal compartment balancing type I IFN-induced inhibition of tissue repair processes.