Signaling to heme oxygenase-1 and its anti-inflammatory therapeutic potential

Heme oxygenase (HO)-1 is the inducible isoform of the first and rate-limiting enzyme of heme degradation. Induction of HO-1 protects against the cytotoxicity of oxidative stress and apoptotic cell death. More recently, HO-1 has been recognized to have major immunomodulatory and anti-inflammatory properties, which have been demonstrated in HO-1 knockout mice and a human case of genetic HO-1 deficiency. Beneficial protective effects of HO-1 in inflammation are not only mediated via enzymatic degradation of proinflammatory free heme, but also via production of the anti-inflammatory compounds bilirubin and carbon monoxide. The immunomodulatory role of HO-1 is associated with its cell type-specific functions in myeloid cells (eg. macrophages and monocytes) and in endothelial cells, as both cell types are crucially involved in the regulation of inflammatory responses. This review covers the molecular mechanisms and signaling pathways that are involved in HO-1 gene expression. In particular, it is discussed how redox-dependent transcriptional activators such as NF-E2 related factor 2 (Nrf2), NF-κB and AP-1 along with the transcription repressor BTB and CNC homologue 1 (Bach1) control the inducible HO-1 gene expression. The role of central pro- and anti-inflammatory cellular signaling cascades including p38 MAPK and phosphatidylinositol-3 kinase (PI3K)/Akt in HO-1 regulation is highlighted. Finally, emerging strategies that apply targeted pharmacological induction of HO-1 for therapeutic interventions in inflammatory conditions are summarized.