Heme oxygenase-1: its therapeutic roles in inflammatory diseases

Abstract

Heme oxygenase (HO)-1 is an inducible enzyme that catalyzes the first and rate-limiting step in the oxidative degradation of free heme into ferrous iron, carbon monoxide (CO), and biliverdin (BV), the latter being subsequently converted into bilirubin (BR). HO-1, once expressed during inflammation, forms high concentrations of its enzymatic by-products that can influence various biological events, and this expression is proven to be associated with the resolution of inflammation. The degradation of heme by HO-1 itself, the signaling actions of CO, the antioxidant properties of BV/BR, and the sequestration of ferrous iron by ferritin all concertedly contribute to the anti-inflammatory effects of HO-1. This review focuses on the anti-inflammatory mechanisms of HO-1 actions and its roles in inflammatory diseases.

Keywords: bilirubin/biliverdin; carbon monoxide; heme oxygenase-1; inflammation; mitogen-activated protein kinase; nuclear factor E2-related factor-2.

Figure 1

Induction of HO-1 and subsequent production of heme degradation products exert potent anti-oxidative, anti-inflammatory and anti-apoptotic functions for the tissue homeostasis. HO-1 can be expressed by a number of stimuli mainly via MAPK-dependent Nrf2 activation. These inducers of HO-1 include free heme, inflammatory mediators, oxidative stress, IL-10, and some inflammatory drugs. HO-1, once expressed under pathological conditions, can degrade free heme into BV, CO, and Fe²⁺. BV is converted into BR by BV reductase. The iron is rapidly sequestered by ferritin. Heme degradation products have been shown to modulate inflammatory response, perhaps by reducing oxidative stress, blocking MAPK pathways, and suppressing NF-κB activity.