IFN-γ or IFN-α Ameliorates Chronic Proliferative Dermatitis by Inducing Expression of Linear Ubiquitin Chain Assembly Complex
IFN-γ or IFN-α Ameliorates Chronic Proliferative Dermatitis by Inducing Expression of Linear Ubiquitin Chain Assembly Complex
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DOI：
10.4049/jimmunol.1302308
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发表时间：
2014-04-15
影响因子：
4.4
通讯作者：
Iwai, Kazuhiro
中科院分区：
文献类型：
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作者：
Tamiya, Hironari;Terao, Mika;Iwai, Kazuhiro
线性泛素链组装复合物（LUBAC）泛素连接酶复合物由HOIL-1 L相互作用蛋白（HOIP）、血红素氧化IRP 2泛素连接酶-1L（HOIL-1 L）和SHANK相关RH结构域蛋白组成，特异性产生线性多聚泛素链，并参与NF-κ B活化。缺乏SHANK相关的RH结构域蛋白，这大大减少了HOIP和HOIL-1 L的量，导致小鼠慢性增殖性皮炎（cpdm）。NF-κ B活化受损和细胞凋亡增加与小鼠cpdm的发病机制有关。在这项研究中，我们发现IFN-γ通过诱导HOIP和HOIL-1 L mRNA转录增加LUBAC的量，并增强野生型和/或cpdm小鼠胚胎成纤维细胞、角质形成细胞和骨髓源性巨噬细胞中信号诱导的NF-κ B活化;然而，IFN-γ未能增强缺乏LUBAC线性多泛素化活性的小鼠胚胎成纤维细胞中的NF-κ B活化。此外，S。C.将IFN-γ注射到cpdm小鼠的皮肤中3周，增加HOIP的量，抑制细胞凋亡，并改善皮炎。通过IFN-γ注射抑制角质形成细胞凋亡抑制了cpdm小鼠皮肤中的中性粒细胞、巨噬细胞和肥大细胞浸润以及TNF-α的量。类似地，IFN-α还增强HOIP的量以及NF-κ B活化，抑制细胞凋亡，并改善cpdm皮炎。这些结果表明IFN通过增加HOIP和HOIL-1 L的表达以及LUBAC的线性多聚泛素化活性来增强NF-κ B活化并改善cpdm皮炎。
The linear ubiquitin chain assembly complex (LUBAC) ubiquitin ligase complex, composed of HOIL-1L-interacting protein (HOIP), heme-oxidized IRP2 ubiquitin ligase-1L (HOIL-1L), and SHANK-associated RH domain protein, specifically generates linear polyubiquitin chains and is involved in NF-kappa B activation. Lack of SHANK-associated RH domain protein, which drastically reduces the amount of HOIP and HOIL-1L, causes chronic proliferative dermatitis (cpdm) in mice. Impaired NF-kappa B activation and augmented apoptosis have been implicated in the pathogenesis of cpdm in mice. In this study, we found that IFN-gamma increased the amount of LUBAC by inducing HOIP and HOIL-1L mRNA transcription and enhanced the signal-induced NF-kappa B activation in embryonic fibroblasts, keratinocytes, and bone marrow-derived macrophages from wild-type and/ or cpdm mice; however, IFN-gamma failed to augment NF-kappa B activation in mouse embryonic fibroblasts lacking linear polyubiquitination activity of LUBAC. Moreover, s. c. injection of IFN-gamma for 3 wk into the skin of cpdm mice increased the amount of HOIP, suppressed apoptosis, and ameliorated the dermatitis. Inhibition of keratinocyte apoptosis by IFN-gamma injection suppressed neutrophil, macrophage, and mast cell infiltration and the amount of TNF-alpha in the skin of cpdm mice. Similarly, IFN-alpha also enhanced the amount of HOIP as well as NF-kappa B activation, inhibited apoptosis, and ameliorated cpdm dermatitis. These results indicate that the IFNs enhance NF-kappa B activation and ameliorate cpdm dermatitis by augmenting expression of HOIP and HOIL-1L and linear polyubiquitination activity of LUBAC.