Limits...
Go green: the anti-inflammatory effects of biliverdin reductase.

Wegiel B, Otterbein LE - Front Pharmacol (2012)

Bottom Line: Biliverdin (BV) has emerged as a cytoprotective and important anti-inflammatory molecule.In macrophages, BVR is regulated by its substrate BV which leads to activation of the PI3K-Akt-IL-10 axis and inhibition of TLR4 expression via direct binding of BVR to the TLR4 promoter.In this review, we will summarize recent findings on the role of BVR and the bile pigments in inflammation in context with its activity as an enzyme, receptor, and transcriptional regulator.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Transplant Institute, Beth Israel Deaconess Medical Center Boston, MA, USA.

ABSTRACT
Biliverdin (BV) has emerged as a cytoprotective and important anti-inflammatory molecule. Conversion of BV to bilirubin (BR) is catalyzed by biliverdin reductase (BVR) and is required for the downstream signaling and nuclear localization of BVR. Recent data by others and us make clear that BVR is a critical regulator of innate immune responses resulting from acute insult and injury and moreover, that a lack of BVR results in an enhanced proinflammatory phenotype. In macrophages, BVR is regulated by its substrate BV which leads to activation of the PI3K-Akt-IL-10 axis and inhibition of TLR4 expression via direct binding of BVR to the TLR4 promoter. In this review, we will summarize recent findings on the role of BVR and the bile pigments in inflammation in context with its activity as an enzyme, receptor, and transcriptional regulator.

No MeSH data available.


Related in: MedlinePlus

A role of BV in activation of PI3K–Akt through cell surface BVR to elicit anti-inflammatory effects. BVR is expressed on the cell surface of macrophages and mediates the anti-inflammatory and cytoprotective signaling of BV. BV is converted to BR by BVRsurf, which drives the recruitment and activation of PI3K–p85α/p110α to BVR to increase the IL-10 levels.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3306015&req=5

Figure 1: A role of BV in activation of PI3K–Akt through cell surface BVR to elicit anti-inflammatory effects. BVR is expressed on the cell surface of macrophages and mediates the anti-inflammatory and cytoprotective signaling of BV. BV is converted to BR by BVRsurf, which drives the recruitment and activation of PI3K–p85α/p110α to BVR to increase the IL-10 levels.

Mentions: Biliverdin reductase has been known for many decades as the second enzyme in the heme degradation pathway necessary for conversion of BV to BR (Frydman et al., 1987; Bell and Maines, 1988) which serves as both a radical scavenger (Stocker et al., 1987), but is also critical in lipid emulsion during digestion. There are two isoforms of BVR. BVR-A, which catalyzes conversion of BV-a specifically and is expressed in the majority of adult tissues and inducible with stress, and BVR-B which is present during embryogenesis and is an isoform specific for the BV-d and b isomers. Both enzymes catalyze reduction of a double-bond between the pyrrole ring into a single-bond using NADH or NADPH as electron donors dependent on a pH optima (6.75 and 8.7, respectively; McCoubrey et al., 1995). BR and BV, through BVR have been shown to prevent cellular senescence (Kim et al., 2011) and apoptosis (Jansen et al., 2010). Regulation of HO-1 and BVR expression and their enzymatic activity is critical for function of the heme degradation pathway. BVR expression is regulated negatively by NF-κB activation and positively by hypoxia-mediated HIF1α stabilization and specific HRE binding sites in the BVR promoter (Gibbs et al., 2010). BVR is strongly induced by its substrate, biliverdin as well as other agents that induce oxidative stress including LPS, heavy metals, and toxins (Maines et al., 2001; Wegiel et al., 2009). BVR has also been demonstrated to be the target for statins with this interaction leading to significant cognitive benefits in a preclinical model of Alzheimer’s disease (Barone et al., 2012). BVR is expressed ubiquitously in all tissues under basal conditions with high levels in the reticulo-macrophages in the spleen and liver. BVR can also be induced. We view this as placing BVR in the category of stress response genes, which is supported by the multiplicity of its functions within the cell, particularly in the context of inflammation. BVR is localized in different cellular compartments in response to stress. BVR has been detected in the membrane (Kim et al., 2004; Wegiel et al., 2009), cytoplasm/ER, mitochondria (Converso et al., 2006), and nucleus (Maines et al., 2001; Ahmad et al., 2002; Lerner-Marmarosh et al., 2008) and its translocation between different cellular compartments is regulated by nitrosylation, lipid modification, or phosphorylation (Wegiel et al., 2009, 2011). Importantly, BV induces NO generation allowing for the stabilization and translocation of BVR to the nucleus (Wegiel et al., 2011). We showed that BVR is strongly induced upon bacteria endotoxin treatment both in the nucleus and on the cell surface (BVRsurf). BVRsurf is newly characterized as an important isoform of BVR, which functions as a tyrosine kinase receptor-mediated signaling dimer in the membrane to bind and convert BV to BR. Simultaneously, with BV binding, BVR cross-phosphorylates Y 198MKM motifs allowing for interaction with PI3K p85α (Lerner-Marmarosh et al., 2005; Maines, 2007; Wegiel et al., 2009; Figure 1).


Go green: the anti-inflammatory effects of biliverdin reductase.

Wegiel B, Otterbein LE - Front Pharmacol (2012)

A role of BV in activation of PI3K–Akt through cell surface BVR to elicit anti-inflammatory effects. BVR is expressed on the cell surface of macrophages and mediates the anti-inflammatory and cytoprotective signaling of BV. BV is converted to BR by BVRsurf, which drives the recruitment and activation of PI3K–p85α/p110α to BVR to increase the IL-10 levels.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3306015&req=5

Figure 1: A role of BV in activation of PI3K–Akt through cell surface BVR to elicit anti-inflammatory effects. BVR is expressed on the cell surface of macrophages and mediates the anti-inflammatory and cytoprotective signaling of BV. BV is converted to BR by BVRsurf, which drives the recruitment and activation of PI3K–p85α/p110α to BVR to increase the IL-10 levels.
Mentions: Biliverdin reductase has been known for many decades as the second enzyme in the heme degradation pathway necessary for conversion of BV to BR (Frydman et al., 1987; Bell and Maines, 1988) which serves as both a radical scavenger (Stocker et al., 1987), but is also critical in lipid emulsion during digestion. There are two isoforms of BVR. BVR-A, which catalyzes conversion of BV-a specifically and is expressed in the majority of adult tissues and inducible with stress, and BVR-B which is present during embryogenesis and is an isoform specific for the BV-d and b isomers. Both enzymes catalyze reduction of a double-bond between the pyrrole ring into a single-bond using NADH or NADPH as electron donors dependent on a pH optima (6.75 and 8.7, respectively; McCoubrey et al., 1995). BR and BV, through BVR have been shown to prevent cellular senescence (Kim et al., 2011) and apoptosis (Jansen et al., 2010). Regulation of HO-1 and BVR expression and their enzymatic activity is critical for function of the heme degradation pathway. BVR expression is regulated negatively by NF-κB activation and positively by hypoxia-mediated HIF1α stabilization and specific HRE binding sites in the BVR promoter (Gibbs et al., 2010). BVR is strongly induced by its substrate, biliverdin as well as other agents that induce oxidative stress including LPS, heavy metals, and toxins (Maines et al., 2001; Wegiel et al., 2009). BVR has also been demonstrated to be the target for statins with this interaction leading to significant cognitive benefits in a preclinical model of Alzheimer’s disease (Barone et al., 2012). BVR is expressed ubiquitously in all tissues under basal conditions with high levels in the reticulo-macrophages in the spleen and liver. BVR can also be induced. We view this as placing BVR in the category of stress response genes, which is supported by the multiplicity of its functions within the cell, particularly in the context of inflammation. BVR is localized in different cellular compartments in response to stress. BVR has been detected in the membrane (Kim et al., 2004; Wegiel et al., 2009), cytoplasm/ER, mitochondria (Converso et al., 2006), and nucleus (Maines et al., 2001; Ahmad et al., 2002; Lerner-Marmarosh et al., 2008) and its translocation between different cellular compartments is regulated by nitrosylation, lipid modification, or phosphorylation (Wegiel et al., 2009, 2011). Importantly, BV induces NO generation allowing for the stabilization and translocation of BVR to the nucleus (Wegiel et al., 2011). We showed that BVR is strongly induced upon bacteria endotoxin treatment both in the nucleus and on the cell surface (BVRsurf). BVRsurf is newly characterized as an important isoform of BVR, which functions as a tyrosine kinase receptor-mediated signaling dimer in the membrane to bind and convert BV to BR. Simultaneously, with BV binding, BVR cross-phosphorylates Y 198MKM motifs allowing for interaction with PI3K p85α (Lerner-Marmarosh et al., 2005; Maines, 2007; Wegiel et al., 2009; Figure 1).

Bottom Line: Biliverdin (BV) has emerged as a cytoprotective and important anti-inflammatory molecule.In macrophages, BVR is regulated by its substrate BV which leads to activation of the PI3K-Akt-IL-10 axis and inhibition of TLR4 expression via direct binding of BVR to the TLR4 promoter.In this review, we will summarize recent findings on the role of BVR and the bile pigments in inflammation in context with its activity as an enzyme, receptor, and transcriptional regulator.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Transplant Institute, Beth Israel Deaconess Medical Center Boston, MA, USA.

ABSTRACT
Biliverdin (BV) has emerged as a cytoprotective and important anti-inflammatory molecule. Conversion of BV to bilirubin (BR) is catalyzed by biliverdin reductase (BVR) and is required for the downstream signaling and nuclear localization of BVR. Recent data by others and us make clear that BVR is a critical regulator of innate immune responses resulting from acute insult and injury and moreover, that a lack of BVR results in an enhanced proinflammatory phenotype. In macrophages, BVR is regulated by its substrate BV which leads to activation of the PI3K-Akt-IL-10 axis and inhibition of TLR4 expression via direct binding of BVR to the TLR4 promoter. In this review, we will summarize recent findings on the role of BVR and the bile pigments in inflammation in context with its activity as an enzyme, receptor, and transcriptional regulator.

No MeSH data available.


Related in: MedlinePlus