Rebholz Bernd, Kehe Kai, Ruzicka Thomas, Rupec Rudolf A
Department of Dermatology and Allergology, Ludwig-Maximilian-University Munich, Munich, Germany.
J Invest Dermatol. 2008 Jul;128(7):1626-32. doi: 10.1038/sj.jid.5701234. Epub 2008 Jan 17.
Sulfur mustard (SM) is a strong vesicant that has been used as a chemical warfare agent. To understand the molecular mechanisms that underlie the inflammatory skin reaction in response to SM, we analyzed the activation pattern of the NF-kappaB and mitogen-activated protein kinase (MAPK) pathways. Keratinocytes responded with an induction of the canonical NF-kappaB pathway, including activation of IkappaB kinase 2, followed by phosphorylation and degradation of IkappaBalpha and of the transactivating subunit RelA at Ser536. The biphasic NF-kappaB response was strictly dependent on the transactivating subunit RelA, as demonstrated by keratinocytes lacking RelA. Parallel to NF-kappaB activation, we observed an induction of the Raf-1/MEK1/2/ERK1/2/MSK1 and MKK3/6/p38/MSK1 pathways. Although mitogen and stress-activated kinase 1 has been described as a RelA kinase with Ser276 as its target, this site remained unphosphorylated in response to SM. A further MAPK pathway induced by SM was the MKK4/7/JNK1/2 pathway, which resulted in phosphorylation of the transcription factor activating transcription factor-2, but not c-Jun. Our results indicate that SM induces a complex cellular response in keratinocytes, with the activation of three MAPK pathways and the NF-kappaB pathway.
硫芥（SM）是一种强效的发泡剂，曾被用作化学战剂。为了解SM引发的炎症性皮肤反应的分子机制，我们分析了核因子κB（NF-κB）和丝裂原活化蛋白激酶（MAPK）信号通路的激活模式。角质形成细胞通过经典NF-κB信号通路的诱导做出反应，包括IκB激酶2的激活，随后IκBα以及转录激活亚基RelA在Ser536位点发生磷酸化和降解。缺乏RelA的角质形成细胞表明，双相NF-κB反应严格依赖于转录激活亚基RelA。与NF-κB激活同时，我们观察到Raf-1/MEK1/2/ERK1/2/MSK1和MKK3/6/p38/MSK1信号通路的诱导。尽管有研究称丝裂原和应激激活激酶1是以Ser276为靶点的RelA激酶，但在SM刺激下该位点并未发生磷酸化。SM诱导的另一条MAPK信号通路是MKK4/7/JNK1/2信号通路，该通路导致转录因子激活转录因子-2发生磷酸化，但c-Jun未被磷酸化。我们的结果表明，SM在角质形成细胞中诱导了复杂的细胞反应，激活了三条MAPK信号通路和NF-κB信号通路。
