| First Author | Seldon MP | Year | 2007 |
| Journal | J Immunol | Volume | 179 |
| Issue | 11 | Pages | 7840-51 |
| PubMed ID | 18025230 | Mgi Jnum | J:155207 |
| Mgi Id | MGI:4412457 | Doi | 10.4049/jimmunol.179.11.7840 |
| Citation | Seldon MP, et al. (2007) Heme oxygenase-1 inhibits the expression of adhesion molecules associated with endothelial cell activation via inhibition of NF-kappaB RelA phosphorylation at serine 276. J Immunol 179(11):7840-51 |
| abstractText | Heme oxygenase-1 (HO-1; encoded by the Hmox1 gene) catalyzes the degradation of free heme into biliverdin, via a reaction that releases iron (Fe) and carbon monoxide. We report that HO-1 down-regulates the proinflammatory phenotype associated with endothelial cell (EC) activation by reducing intracellular nonprotein-bound Fe (labile Fe). EC isolated from Hmox1(-/-) mice have higher levels of intracellular labile Fe and reactive oxygen species (ROS) as compared with EC isolated from Hmox1(+/+) mice. Basal and TNF-induced expression of VCAM-1, ICAM-1, and E-selectin were increased in Hmox1(-/-) vs Hmox1(+/+) EC, an effect reversed by Fe chelation using deferoxamine mesylate (DFO). Fe chelation inhibits TNF-driven transcription of Vcam-1, Icam-1, and E-selectin, as assessed using luciferase reporter assays. This effect is associated with inhibition of the transcription factor NF-kappaB via a mechanism that is not associated with the inhibition of IkappaBalpha phosphorylation/degradation or NF-kappaB (i.e., RelA) nuclear translocation, although it affects very modestly NF-kappaB binding to DNA kappaB consensus sequences in the Vcam-1 and E-selectin promoters. HO-1 inhibits NF-kappaB (i.e., RelA) phosphorylation at Ser(276), a phosphoacceptor that is critical to sustain TNF-driven NF-kappaB activity in EC. This effect was mimicked by Fe chelation as well as by antioxidants (N-acetylcysteine). In conclusion, we demonstrate a novel mechanism via which HO-1 down-modulates the proinflammatory phenotype of activated EC, i.e., the inhibition of RelA phosphorylation at Ser(276). |
