Meynard Delphine, Sun Chia Chi, Wu Qifang, Chen Wenjie, Chen Shanzhuo, Nelson Caroline N, Waters Michael J, Babitt Jodie L, Lin Herbert Y
Program in Anemia Signaling Research, Division of Nephrology, Program in Membrane Biology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
Institute for Molecular Bioscience, University of Queensland, St. Lucia, Australia.
PLoS One. 2013 Dec 23;8(12):e82127. doi: 10.1371/journal.pone.0082127. eCollection 2013.
TMPRSS6 is a regulated gene, with a crucial role in the regulation of iron homeostasis by inhibiting hepcidin expression. The main regulator of iron homeostasis, the antimicrobial peptide hepcidin, which also has a role in immunity, is directly upregulated by inflammation. In this study, we analyzed whether inflammation is also a modulator of TMPRSS6 expression in vitro and in vivo and we determined the mechanism of this regulation A Human Hepatoma cell line was treated with interleukin-6 and mice were injected with lipopolysaccharide and TMPRSS6 expression and the regulatory mechanism were addressed. In this study, we demonstrate that inflammation downregulates TMPRSS6 expression in vitro and in vivo. The downregulation of Tmprss6 by inflammation in mice is not dependent on the Bmp-Smad pathway but occurs through a decrease in Stat5 phosphorylation. Moreover, Stat5 positively regulates Tmprss6 expression directly by binding to a Stat5 element located on the Tmprss6 promoter. Importantly, our results highlight the functional role of inflammatory modulation of TMPRSS6 expression in the regulation of hepcidin. TMPRSS6 inhibition via decreased STAT5 phosphorylation may be an additional mechanism by which inflammation stimulates hepcidin expression to regulate iron homeostasis and immunity.
跨膜丝氨酸蛋白酶6（TMPRSS6）是一个受调控的基因，在通过抑制铁调素表达来调节铁稳态中起关键作用。铁稳态的主要调节因子，即抗菌肽铁调素，它在免疫中也发挥作用，会被炎症直接上调。在本研究中，我们分析了炎症在体外和体内是否也是TMPRSS6表达的调节因子，并确定了这种调节的机制。用人白细胞介素-6处理人肝癌细胞系，给小鼠注射脂多糖，探讨TMPRSS6表达及调节机制。在本研究中，我们证明炎症在体外和体内均下调TMPRSS6表达。炎症在小鼠中对Tmprss6的下调不依赖于骨形态发生蛋白（Bmp）-Smad信号通路，而是通过信号转导和转录激活因子5（Stat5）磷酸化的减少而发生。此外，Stat5通过与位于Tmprss6启动子上的Stat5元件结合直接正向调节Tmprss6表达。重要的是，我们的结果突出了炎症调节TMPRSS6表达在铁调素调节中的功能作用。通过降低STAT5磷酸化来抑制TMPRSS6可能是炎症刺激铁调素表达以调节铁稳态和免疫的另一种机制。
