Hepcidin regulation by innate immune and infectious stimuli
Hepcidin regulation by innate immune and infectious stimuli
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DOI：
10.1182/blood-2011-04-351957
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发表时间：
2011-10-13
期刊：
影响因子：
20.3
通讯作者：
Drakesmith, Hal
中科院分区：
文献类型：
--
作者：
Armitage, Andrew E.;Eddowes, Lucy A.;Drakesmith, Hal
铁调素控制铁的水平和分布，铁的可用性可以影响感染的结果。我们在体外和体内研究了感染相关细胞因子、病原体衍生分子和整个病原体对铁调素的调节作用。我们发现，IL-22（一种与细胞外感染反应有关的效应细胞因子）在人肝癌细胞中引起不依赖于 IL-6 的铁调素上调，表明它可能是另一种炎症性铁调素激动剂。与 IL-6 一样，IL-22 引起 STAT3 磷酸化，并与 BMP6 协同增强铁调素诱导。在人类白细胞中，IL-6 引起有效、短暂的铁调素上调，而 TGF-β 1 会增强这种上调。病原体衍生的 TLR 激动剂也会以 IL-6 依赖性方式刺激铁调素，尤其是 TLR5 激动剂鞭毛蛋白。相反，热灭活的白色念珠菌菌丝对白细胞铁调素的诱导不依赖于IL-6，但部分依赖于TGF-β。在小鼠急性全身性念珠菌病模型中，白色念珠菌强烈刺激铁调素，并伴随转铁蛋白饱和度的大幅降低。同样，在急性鼠 A/PR/8/34 病毒 (H1N1) 感染期间，铁调素上调，同时血清铁降低。这种细胞内病原体还刺激白细胞和肝癌细胞中铁调素的表达。总之，这些结果表明铁调素诱导代表了对急性感染的先天免疫反应的一个组成部分，有可能影响疾病的发病机制。 （血。2011；118（15）：4129-4139）
Hepcidin controls the levels and distribution of iron, an element whose availability can influence the outcome of infections. We investigated hepcidin regulation by infection-associated cytokines, pathogen-derived molecules, and whole pathogens in vitro and in vivo. We found that IL-22, an effector cytokine implicated in responses to extracellular infections, caused IL-6-independent hepcidin up-regulation in human hepatoma cells, suggesting it might represent an additional inflammatory hepcidin agonist. Like IL-6, IL-22 caused phosphorylation of STAT3 and synergized with BMP6 potentiating hepcidin induction. In human leukocytes, IL-6 caused potent, transient hepcidin up-regulation that was augmented by TGF-beta 1. Pathogen-derived TLR agonists also stimulated hepcidin, most notably the TLR5 agonist flagellin in an IL-6-dependent manner. In contrast, leukocyte hepcidin induction by heat-killed Candida albicans hyphae was IL-6-independent, but partially TGF-beta-dependent. In a murine acute systemic candidiasis model, C albicans strongly stimulated hepcidin, accompanied by a major reduction in transferrin saturation. Similarly, hepcidin was up-regulated with concomitant lowering of serum iron during acute murine Influenza A/PR/8/34 virus (H1N1) infection. This intracellular pathogen also stimulated hepcidin expression in leukocytes and hepatoma cells. Together, these results indicate that hepcidin induction represents a component of the innate immune response to acute infection, with the potential to affect disease pathogenesis. (Blood. 2011; 118(15):4129-4139)