Rémy Séverine, Blancou Philippe, Tesson Laurent, Tardif Virginie, Brion Régis, Royer Pierre Joseph, Motterlini Roberto, Foresti Roberta, Painchaut Marion, Pogu Sylvie, Gregoire Marc, Bach Jean Marie, Anegon Ignacio, Chauveau Christine
Institut National de Santé et de Recherche Médicale, Unité 643, Nantes, France.
J Immunol. 2009 Feb 15;182(4):1877-84. doi: 10.4049/jimmunol.0802436.
Heme oxygenase-1 (HO-1) exerts its functions via the catabolism of heme into carbon monoxide (CO), Fe(2+), and biliverdin, as well as by depletion of free heme. We have recently described that overexpression of HO-1 is associated with the tolerogenic capacity to dendritic cells (DCs) stimulated by LPS. In this study, we demonstrate that treatment of human monocyte-derived DCs with CO blocks TLR3 and 4-induced phenotypic maturation, secretion of proinflammatory cytokines, and alloreactive T cell proliferation, while preserving IL-10 production. Treatment of DCs with biliverdin, bilirubin, and deferoxamine or replenishing intracellular heme stores had no effect on DC maturation. HO-1 and CO inhibited LPS-induced activation of the IFN regulatory factor 3 pathway and their effects were independent of p38, ERK, and JNK MAPK. HO-1 and CO treatment also inhibited mouse DC maturation in vitro and mouse DC immunogenic properties in vivo, as shown by adoptive cell transfer in a transgenic model of induced diabetes. Thus, for the first time, our data show that CO treatment inhibits DC immunogenicity induced by TLR ligands and that blockade of IFN regulatory factor 3 is associated with this effect.
血红素加氧酶-1（HO-1）通过将血红素分解为一氧化碳（CO）、亚铁离子（Fe2+）和胆绿素，以及通过消耗游离血红素发挥其功能。我们最近报道，HO-1的过表达与脂多糖刺激的树突状细胞（DC）的致耐受性能力有关。在本研究中，我们证明用CO处理人单核细胞来源的DC可阻断Toll样受体3（TLR3）和4诱导的表型成熟、促炎细胞因子的分泌以及同种异体反应性T细胞增殖，同时保留白细胞介素-10（IL-10）的产生。用胆绿素、胆红素和去铁胺处理DC或补充细胞内血红素储备对DC成熟没有影响。HO-1和CO抑制脂多糖诱导的干扰素调节因子3（IRF3）信号通路的激活，且它们的作用独立于p38、细胞外信号调节激酶（ERK）和应激活化蛋白激酶（JNK）丝裂原活化蛋白激酶（MAPK）。HO-1和CO处理还抑制了小鼠DC在体外的成熟以及在体内的免疫原性，这在诱导糖尿病的转基因模型中通过过继性细胞转移得到证实。因此，我们的数据首次表明，CO处理可抑制TLR配体诱导的DC免疫原性，且IRF3的阻断与这种效应相关。
