Heme oxygenase-1 modulates the expression of adhesion molecules associated with endothelial cell activation
Heme oxygenase-1 modulates the expression of adhesion molecules associated with endothelial cell activation
复制标题
DOI：
10.4049/jimmunol.172.6.3553
复制
发表时间：
2004-03-15
影响因子：
4.4
通讯作者：
Bach, FH
中科院分区：
文献类型：
--
作者：
Soares, MP;Seldon, MP;Bach, FH
血红素加氧酶-1（HO-1）将血红素的卟啉环裂解为一氧化碳、Fe 2+和胆绿素，然后将胆绿素转化为胆红素。血红素来源的Fe ~（2+）诱导铁螯合蛋白铁蛋白的表达并激活ATP酶Fe ~（2+）分泌泵，从而降低细胞内游离Fe ~（2+）含量。基于胆红素的抗氧化作用和细胞游离Fe 2+的减少，我们质疑HO-1是否会调节与内皮细胞（EC）活化相关的促炎基因的表达。我们专门针对基因E-选择素（CD 62）、ICAM-1（CD 54）和VCAM-1（CD 106）检验了这一假设。我们发现HO-1在EC中的过表达抑制TNF-α介导的E-选择素和VCAM-1，但不ICAM-1的表达，如在RNA和蛋白质水平测试。血红素驱动的HO-1表达与过表达的HO-1具有相似的作用。此外，HO-1抑制NF-κ B的激活，NF-κ B是EC中TNF-α介导的这些基因上调所需的转录因子。胆红素和/或Fe 2+螯合模拟HO-1的影响，而胆绿素或一氧化碳没有。总之，HO-1通过与抑制NF-κ B活化相关的机制抑制与EC活化相关的促炎基因的表达。HO-1的这种作用由胆红素和/或细胞内游离Fe 2+的减少介导，但可能不是由胆绿素或一氧化碳介导的。
Heme oxygenase-1 (HO-1) cleaves the porphyrin ring of heme into carbon monoxide, Fe2+, and biliverdin, which is then converted into bilirubin. Heme-derived Fe-2+ induces the expression of the iron-sequestering protein ferritin and activates the ATPase Fe2+ -secreting pump, which decrease intracellular free Fe2+ content. Based on the antioxidant effect of bilirubin and that of decreased free cellular Fe2+, we questioned whether HO-1 would modulate the expression of proinflammatory genes associated with endothelial cell (EC) activation. We tested this hypothesis specifically for the genes E-selectin (CD62), ICAM-1 (CD54), and VCAM-1 (CD106). We found that HO-1 overexpression in EC inhibited TNF-alpha-mediated E-selectin and VCAM-1, but not ICAM-1 expression, as tested at the RNA and protein level. Heme-driven HO-1 expression had similar effects to those of overexpressed HO-1. In addition, HO-1 inhibited the activation of NF-kappaB, a transcription factor required for TNF-a-mediated up-regulation of these genes in EC. Bilirubin and/or Fe2+ chelation mimicked the effects of HO-1, whereas biliverdin or carbon monoxide did not. In conclusion, HO-1 inhibits the expression of proinflammatory genes associated with EC activation via a mechanism that is associated with the inhibition of NF-kappaB activation. This effect of HO-1 is mediated by bilirubin and/or by a decrease of free intracellular Fe2+ but probably not by biliverdin or carbon monoxide.