Heme oxygenase-1 modulates the expression of adhesion molecules associated with endothelial cell activation.
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 Fe2+ 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-alpha-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.
Soares
Miguel P
MP
Immunobiology Research Center, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA. mpsoares@igc.gulbenkian.pt
Seldon
Mark P
MP
Gregoire
Isabel Pombo
IP
Vassilevskaia
Tatiana
T
Berberat
Pascal O
PO
Yu
Jia
J
Tsui
Tung-Yu
TY
Bach
Fritz H
FH
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001663:Bilirubin / Q000494:pharmacology; D002248:Carbon Monoxide / Q000494:pharmacology; D002417:Cattle; D015815:Cell Adhesion Molecules; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D019040:E-Selectin / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D006418:Heme / Q000494:pharmacology; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051547:Heme Oxygenase-1; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007502:Iron Chelating Agents / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000276:immunology; D008565:Membrane Proteins; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000494:pharmacology; D013552:Swine; D014161:Transduction, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases
D015815:Cell Adhesion Molecules; D019040:E-Selectin; D007502:Iron Chelating Agents; D008565:Membrane Proteins; D016328:NF-kappa B; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D006418:Heme; D002248:Carbon Monoxide; C496541:HMOX1 protein, human; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D001663:Bilirubin