Department of Internal Medicine I, Clinical Immunology and Infectious Diseases, Medical University of Innsbruck, Austria.
J Infect Dis. 2011 Sep 1;204(5):685-94. doi: 10.1093/infdis/jir395.
Iron overload can adversely influence the course of infection by increasing microbial replication and suppressing antimicrobial immune effector pathways. Recently, we have shown that the calcium channel blocker nifedipine can mobilize tissue iron in mouse models of iron overload. We therefore investigated whether nifedipine treatment affects the course of infection with intracellular bacteria via modulation of iron homeostasis.
The effect of nifedipine on intramacrophage replication of bacteria and modulation of cellular iron homeostasis was investigated in the murine macrophage cell line RAW264.7, and the impact of nifedipine treatment on the course of systemic infection was investigated in C57BL/6 mice in vivo.
In RAW264.7 cells, nifedipine treatment significantly reduced intracellular bacterial survival of Salmonella enterica serovar Typhimurium and Chlamydophila pneumoniae. This could be attributed to the induction of the iron exporter ferroportin 1, which limited the availability of iron for intracellular Salmonella. When C57BL/6 mice were infected intraperitoneally with Salmonella and subsequently injected with nifedipine for 3 consecutive days, bacterial counts in livers and spleens were significantly reduced and survival of the mice significantly was prolonged compared with solvent-treated littermates. Nifedipine treatment increased expression of ferroportin 1 in the spleen, whereas splenic levels of the iron storage protein ferritin and serum iron concentrations were reduced.
Our data provide evidence for a novel mechanism whereby nifedipine enhances host resistance to intracellular pathogens via limitation of iron availability.
铁过载会通过增加微生物复制和抑制抗菌免疫效应途径来不良影响感染过程。最近，我们已经证明钙通道阻滞剂硝苯地平可以在铁过载的小鼠模型中动员组织铁。因此，我们研究了硝苯地平治疗是否通过调节铁稳态来影响细胞内细菌感染的过程。
我们在鼠巨噬细胞系 RAW264.7 中研究了硝苯地平对细菌在巨噬细胞内复制的影响和细胞内铁稳态的调节，并在体内研究了硝苯地平治疗对 C57BL/6 小鼠全身感染过程的影响。
在 RAW264.7 细胞中，硝苯地平处理显著降低了鼠伤寒沙门氏菌和肺炎衣原体的细胞内细菌存活。这可能归因于铁输出蛋白 ferroportin 1 的诱导，这限制了细胞内沙门氏菌的铁可用性。当 C57BL/6 小鼠经腹腔感染沙门氏菌并用硝苯地平连续注射 3 天，肝脏和脾脏中的细菌计数显著减少，与溶剂处理的同窝小鼠相比，小鼠的存活率显著延长。硝苯地平处理增加了脾脏中 ferroportin 1 的表达，而脾脏中铁储存蛋白 ferritin 的水平和血清铁浓度降低。
我们的数据提供了证据表明，硝苯地平通过限制铁的可用性来增强宿主对细胞内病原体的抵抗力，这是一种新的机制。
