From the Laboratório de Inflamação e Imunidade, Departamento de Imunologia, Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil; Instituto de Investigaciones Científicas y Servicios de Alta Tecnologia, 0843-01103 Ciudad de Panamá, Panamá.
From the Laboratório de Inflamação e Imunidade, Departamento de Imunologia, Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil.
J Biol Chem. 2010 Oct 22;285(43):32844-32851. doi: 10.1074/jbc.M110.146076. Epub 2010 Aug 20.
Infectious diseases that cause hemolysis are among the most threatening human diseases, because of severity and/or global distribution. In these conditions, hemeproteins and heme are released, but whether heme affects the inflammatory response to microorganism molecules remains to be characterized. Here, we show that heme increased the lethality and cytokine secretion induced by LPS in vivo and enhanced the secretion of cytokines by macrophages stimulated with various agonists of innate immune receptors. Activation of nuclear factor κB (NF-κB) and MAPKs and the generation of reactive oxygen species were essential to the increase in cytokine production induced by heme plus LPS. This synergistic effect of heme and LPS was blocked by a selective inhibitor of spleen tyrosine kinase (Syk) and was abrogated in dendritic cells deficient in Syk. Moreover, inhibition of Syk and the downstream molecules PKC and PI3K reduced the reactive oxygen species generation by heme. Our results highlight a mechanism by which heme amplifies the secretion of cytokines triggered by microbial molecule activation and indicates possible pathways for therapeutic intervention during hemolytic infectious diseases.
引起溶血的传染病是对人类最具威胁的疾病之一，因为其严重性和/或全球分布。在这些情况下，血红素蛋白和血红素被释放，但血红素是否影响对微生物分子的炎症反应仍有待研究。在这里，我们表明血红素增加了 LPS 在体内诱导的致死率和细胞因子分泌，并增强了各种先天免疫受体激动剂刺激的巨噬细胞分泌细胞因子。核因子 kappaB (NF-κB) 和 MAPKs 的激活以及活性氧的产生对于血红素加 LPS 诱导的细胞因子产生增加是必不可少的。血红素和 LPS 的这种协同作用被脾酪氨酸激酶 (Syk) 的选择性抑制剂阻断，并且在缺乏 Syk 的树突状细胞中被废除。此外，抑制 Syk 和下游分子 PKC 和 PI3K 减少了血红素产生的活性氧。我们的结果强调了血红素放大微生物分子激活引发的细胞因子分泌的机制，并为溶血性传染病期间的治疗干预提供了可能的途径。
