Deferoxamine attenuates lipopolysaccharide-induced inflammatory responses and protects against endotoxic shock in mice.
To examine the role of the intracellular labile iron pool (LIP) in the induction of inflammatory responses, we investigated the anti-inflammatory effect of the iron chelator deferoxamine (DFO) on lipopolysaccharide (LPS)-induced inflammatory responses in RAW264.7 macrophage cells and endotoxic shock in mice in the present study. Our data showed that DFO significantly decreased LPS-induced LIP and ROS upregulation. We then found that DFO inhibited phosphorylation of MAP kinases such as ERK and p38 and also inhibited the activation of NF-κB induced by LPS. Furthermore, the production of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), nitric oxide (NO) and prostaglandin E2 (PGE2) induced by LPS was inhibited by DFO in RAW264.7 macrophages. Administration of DFO significantly decreased the mortality and improved the survival of septic mice with lethal endotoxemia in LPS-injected mice. These results demonstrate that iron plays a pivotal role in the induction of inflammatory responses and against septic shock. DFO has effective inhibitory effect on the production of inflammatory mediators via suppressing activation of MAPKs and NF-κB signaling pathways; it also has a protective effect on LPS-induced endotoxic shock in mice. Our findings open doors to further studies directed at exploring a new class of drugs against septic shock or other inflammatory diseases by modulating cellular chelatable iron.
Laboratory of Molecular Iron Metabolism, Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, Key Laboratory of Molecular and Cellular Biology of Ministry of Education, College of Life Science, Hebei Normal University, Shijiazhuang 050024, PR China.
Shengnan
S
Wang
Laboratory of Molecular Iron Metabolism, Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, Key Laboratory of Molecular and Cellular Biology of Ministry of Education, College of Life Science, Hebei Normal University, Shijiazhuang 050024, PR China.
Caizhi
C
Liu
Laboratory of Molecular Iron Metabolism, Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, Key Laboratory of Molecular and Cellular Biology of Ministry of Education, College of Life Science, Hebei Normal University, Shijiazhuang 050024, PR China.
Shuhong
S
Pan
Laboratory of Molecular Iron Metabolism, Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, Key Laboratory of Molecular and Cellular Biology of Ministry of Education, College of Life Science, Hebei Normal University, Shijiazhuang 050024, PR China.
Qing
Q
Miao
Laboratory of Molecular Iron Metabolism, Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, Key Laboratory of Molecular and Cellular Biology of Ministry of Education, College of Life Science, Hebei Normal University, Shijiazhuang 050024, PR China.
Jianqi
J
Xue
Laboratory of Molecular Iron Metabolism, Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, Key Laboratory of Molecular and Cellular Biology of Ministry of Education, College of Life Science, Hebei Normal University, Shijiazhuang 050024, PR China.
Jingna
J
Xun
Laboratory of Molecular Iron Metabolism, Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, Key Laboratory of Molecular and Cellular Biology of Ministry of Education, College of Life Science, Hebei Normal University, Shijiazhuang 050024, PR China.
Yuling
Y
Zhang
Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing 210046, China.
Yanhong
Y
Gao
Laboratory of Molecular Iron Metabolism, Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, Key Laboratory of Molecular and Cellular Biology of Ministry of Education, College of Life Science, Hebei Normal University, Shijiazhuang 050024, PR China. Electronic address: xlduan0311@163.com.
Xianglin
X
Duan
Laboratory of Molecular Iron Metabolism, Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, Key Laboratory of Molecular and Cellular Biology of Ministry of Education, College of Life Science, Hebei Normal University, Shijiazhuang 050024, PR China. Electronic address: fanyumei@mail.hebtu.edu.cn.
Yumei
Y
Fan
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D003676:Deferoxamine / Q000378:metabolism / Q000494:pharmacology*; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000378:metabolism / Q000494:pharmacology*; D008070:Lipopolysaccharides; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D012772:Shock, Septic / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D015398:Signal Transduction; D016019:Survival Analysis; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D053583:Interleukin-1beta; D007502:Iron Chelating Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007501:Iron; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D003676:Deferoxamine; D015232:Dinoprostone
Deferoxamine; Inflammation; Labile iron pool; MAPKs; NF-κB; Reactive oxygen species