Anti-inflammatory effects of HO-1 activity in vascular endothelial cells, commentary on Carbon monoxide donors or heme oxygenase (HO-1) overexpression blocks interleukin-18-mediated NF-κB-PTEN-dependent human cardiac endothelial cell death

In this issue of Free Radical Biology & Medicine, Zabalgoitia et al. show that IL-18-dependent cell death of human microvascular endothelial cells (EC) is due to activation of p38 alpha and NF-kappa B and suppression of p38 beta activity. Most interestingly, IL-18 and herne oxygenase-I (HO-1) activities appear to oppose each other in these cells. IL-18 suppresses HO-1, an effect that is mediated by instability of the HO-1 mRNA. Though the contribution of HO-1 metabolites remains somewhat a mystery, treatment with carbon monoxide releasing molecules (CORMs) also induces these same effects, implicating carbon monoxide (CO) as a major player. HO-1 and CO act to suppress IL-18-mediated activation of p38 alpha and to restore p38 beta activity, which is suppressed by IL-18. Furthermore, HO-1 and CO suppress NF-kappa B activation by IL- 18. This suppression of NF-kappa B reduces levels of PTEN which relieves IL-18-mediated suppression of Akt activity. Thus, HO-1 and CO oppose multiple proinflammatory and pro-cell death effects of IL-18 in human microvascular endothelial cells. The results of this study imply that induction of HO-1 or application of CORMs should be protective to the microvascular endothelium. Clinical trials to test the effects of CORMs in pulmonary inflammation are ongoing. The study by Zabalgoitia et al. provides mechanistic information pertaining to the homeostatic balance of IL-18 and HO-1 activities and may be useful for designing new clinical studies and for interpretation of data from ongoing studies. Published by Elsevier Inc.