Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation
Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation
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DOI：
10.1182/blood-2010-10-313064
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发表时间：
2011-05-05
期刊：
影响因子：
20.3
通讯作者：
Yu, Paul B.
中科院分区：
文献类型：
--
作者：
Steinbicker, Andrea U.;Sachidanandan, Chetana;Yu, Paul B.
炎症性贫血发生在慢性炎症性、感染性或肿瘤性疾病的环境中。在这种高度流行的贫血形式中，包括IL-6在内的炎性细胞因子刺激肝脏中海普西丁的表达，而海普西丁通过使铁蛋白失活来负面调节铁的生物利用度。海普西丁受IL-6和骨形态发生蛋白(BMP)信号的转录调控。我们假设抑制BMP信号可以减少海普西丁的表达，改善与炎症相关的低铁血症和贫血。在人肝癌细胞中，IL-6诱导海普西丁的表达，这种作用可被骨形态发生蛋白I型受体抑制剂LDN-193189或骨形态发生蛋白配体拮抗剂noggin和alk3-fc所抑制。在斑马鱼中，IL-6转基因表达对海普西丁的诱导表达也被LDN-193189抑制。在小鼠中，IL-6或松节油处理增加了海普西丁的表达，降低了血清铁，这一作用可被LDN-193189或ALK3-Fc抑制。慢性松节油治疗导致小细胞性贫血，可通过同时给予LDN-193189预防，或在贫血确诊后给予LDN-193189缓解。我们的研究支持BMP和IL-6共同作用于铁稳态的观点，并提示抑制BMP信号转导可能是治疗炎症性贫血的有效策略。(血。2011；117(18)：4915-4923)
Anemia of inflammation develops in settings of chronic inflammatory, infectious, or neoplastic disease. In this highly prevalent form of anemia, inflammatory cytokines, including IL-6, stimulate hepatic expression of hepcidin, which negatively regulates iron bioavailability by inactivating ferroportin. Hepcidin is transcriptionally regulated by IL-6 and bone morphogenetic protein (BMP) signaling. We hypothesized that inhibiting BMP signaling can reduce hepcidin expression and ameliorate hypoferremia and anemia associated with inflammation. In human hepatoma cells, IL-6-induced hepcidin expression, an effect that was inhibited by treatment with a BMP type I receptor inhibitor, LDN-193189, or BMP ligand antagonists noggin and ALK3-Fc. In zebrafish, the induction of hepcidin expression by transgenic expression of IL-6 was also reduced by LDN-193189. In mice, treatment with IL-6 or turpentine increased hepcidin expression and reduced serum iron, effects that were inhibited by LDN-193189 or ALK3-Fc. Chronic turpentine treatment led to microcytic anemia, which was prevented by concurrent administration of LDN-193189 or attenuated when LDN-193189 was administered after anemia was established. Our studies support the concept that BMP and IL-6 act together to regulate iron homeostasis and suggest that inhibition of BMP signaling may be an effective strategy for the treatment of anemia of inflammation. (Blood. 2011;117(18):4915-4923)