Tumor necrosis factor α inhibits expression of the iron regulating hormone hepcidin in murine models of innate colitis.
Tumor necrosis factor α inhibits expression of the iron regulating hormone hepcidin in murine models of innate colitis.
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DOI：
10.1371/journal.pone.0038136
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Cherayil BJ
中科院分区：
文献类型：
--
作者：
Shanmugam NK;Ellenbogen S;Trebicka E;Wang L;Mukhopadhyay S;Lacy-Hulbert A;Gallini CA;Garrett WS;Cherayil BJ
肝肽激素海普西丁的异常表达是铁稳态的关键调节因素，在炎症性肠病(IBD)等条件下导致贫血。由于对肠道炎症状态下控制海普西丁表达的机制知之甚少，我们试图通过小鼠模型阐明这一问题。研究了两种天然免疫激活引起的肠道炎症--葡聚糖硫酸钠(DSS)诱导的野生型小鼠结肠炎和T-bet/Rag2缺陷型(TRUC)小鼠自发性结肠炎中海普西丁的表达。通过体内中和和用重组细胞因子处理肝细胞系和小鼠来研究肿瘤坏死因子α的作用。在结肠炎期间和给予或中和肿瘤坏死因子α后，检测了海普西丁转录的正调控因子Smad1的表达和激活。在DSS结肠炎过程中，海普西丁的表达随着时间的推移而递减，与全身铁分布的变化有关。在培养的肝细胞和非结肠炎小鼠中，肿瘤坏死因子α抑制了海普西丁的表达，而在直肠结肠炎时中和肿瘤坏死因子α使其表达增加。在TRUC小鼠身上也得到了类似的结果。这些效应包括肿瘤坏死因子α依赖的Smad1蛋白的减少，但不是mR NA。肿瘤坏死因子α在两种不同类型的先天性结肠炎中抑制海普西丁的表达，Smad1蛋白的下调在这一过程中起着重要作用。在T细胞介导的结肠炎中，肿瘤坏死因子α的这种抑制作用可能会被其他因素所取代，因为在后一种形式的肠道炎症中，海普西丁通常上调。
Abnormal expression of the liver peptide hormone hepcidin, a key regulator of iron homeostasis, contributes to the pathogenesis of anemia in conditions such as inflammatory bowel disease (IBD). Since little is known about the mechanisms that control hepcidin expression during states of intestinal inflammation, we sought to shed light on this issue using mouse models. Hepcidin expression was evaluated in two types of intestinal inflammation caused by innate immune activation—dextran sulfate sodium (DSS)-induced colitis in wild-type mice and the spontaneous colitis occurring in T-bet/Rag2-deficient (TRUC) mice. The role of tumor necrosis factor (TNF) α was investigated by in vivo neutralization, and by treatment of a hepatocyte cell line, as well as mice, with the recombinant cytokine. Expression and activation of Smad1, a positive regulator of hepcidin transcription, were assessed during colitis and following administration or neutralization of TNFα. Hepcidin expression progressively decreased with time during DSS colitis, correlating with changes in systemic iron distribution. TNFα inhibited hepcidin expression in cultured hepatocytes and non-colitic mice, while TNFα neutralization during DSS colitis increased it. Similar results were obtained in TRUC mice. These effects involved a TNFα-dependent decrease in Smad1 protein but not mRNA. TNFα inhibits hepcidin expression in two distinct types of innate colitis, with down-regulation of Smad1 protein playing an important role in this process. This inhibitory effect of TNFα may be superseded by other factors in the context of T cell-mediated colitis given that in the latter form of intestinal inflammation hepcidin is usually up-regulated.
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影响因子：
20.3
作者：
Falzacappa, Maria Vittoria Verga;Spasic, Maja Vujic;Muckenthaler, Martina U.
通讯作者：
Muckenthaler, Martina U.
DOI：
10.1097/meg.0b013e328343b885
发表时间：
2011-03-01
影响因子：
2.1
作者：
Oustamanolakis, Pantelis;Koutroubakis, Ioannis E.;Kouroumalis, Elias A.
通讯作者：
Kouroumalis, Elias A.
影响因子：
15.9
作者：
Babitt, Jodie L.;Huang, Franklin W.;Lin, Herbert Y.
通讯作者：
Lin, Herbert Y.
影响因子：
4.8
作者：
Goswami, Tapasree;Andrews, Nancy C.
通讯作者：
Andrews, Nancy C.
影响因子：
82.9
作者：
通讯作者：
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