Biliverdin inhibits activation of NF‐κB: Reversal of inhibition by human biliverdin reductase

Abstract

hBVR functions in the cell as a reductase and as a kinase. In the first capacity, it reduces biliverdin, the product of HO activity, to the effective intracellular antioxidant, bilirubin; as a dual-specificity kinase (S/T/Y) it activates the MAPK and IGF/IRK receptor signal transduction pathways. NF-jB and the MAPK pathway are activated by ROS, which results in the activation of stress-inducible genes, including ho-1. Presently, we report on the negative effect of biliverdin on NF-jB activation and the converse effect of hBVR. Biliverdin, in a concentration-and time-dependent manner, inhibited transcriptional activity of NF-jB in HEK293A cells. Nuclear extracts from biliverdin-treated cells show reduced DNA binding of NF-jB in an electromobility shift assay, whereas extracts from cells treated with TNF-a showed enhanced binding. Coimmunoprecipitation data show hBVR binds to the 65 kDa subunit of NF-jB, and that this is dependent on activation by TNF-a. Overexpression of hBVR enhanced both the basal and TNF-amediated activation of NF-jB and also that of the NF-jB-activated iNOS gene. Also, overexpression of hBVR arrested the cell cycle in the G 1 /G 0 phase and reduced the number of cells in S phase. Similar results were observed with MCF-7 cells. Because of the Janus nature of NF-jB activity in the cell and the inhibitory action of biliverdin, the present findings provide a foundation for therapeutic intervention in inflammatory diseases and cancer that may be attained by preventing reduction of biliverdin. On the other hand, by increasing BVR levels beneficial functions of NF-jB might be augmented. ' 2007 Wiley-Liss, Inc.

Human Biliverdin Reductase Suppresses Goodpasture Antigen-binding Protein (GPBP) Kinase Activity

“…GPBP Phosphorylation Is Attenuated in the Presence of hBVRhBVR functions in TNF-␣-NF-B signaling, wherein it is activated by the cytokine and activates the transcription factor (20,25). GPBP is also activated by TNF-␣ (4).…”

“…The cytokine is an upstream activator of the transcription factor NF-B (23,24). Activation of NF-B by TNF-␣ is inhibited by biliverdin, whereas hBVR reverses the inhibition (25). Notably, a peptide corresponding to the hBVR D-Box motif blocks activation of PKC-in response to TNF-␣ (20).…”

Redox regulation of cellular stress response in multiple sclerosis

“…Iron is reduced to its ferrous state through the action of NADPH cytochrome c P450 reductase. Further degradation of biliverdin to bilirubin occurs through the action of a cytosolic enzyme, biliverdin reductase [48]. HO is present in various tissues with the highest activity in the brain, liver, spleen, and testes.…”

Human biliverdin reductase is an ERK activator; hBVR is an ERK nuclear transporter and is required for MAPK signaling

“…Activation of PKCs and ERK is associated with the induction of AP-1 transcription factors (c-Jun, c-Fos, and ATF-2/CREB), which are downstream targets of MAPK (8). Activation of hBVR has been correlated with the aforementioned AP-1 transcription factor induction and NF-B that acts downstream of the MAPK/PI3K/Aktsignaling cascade (9)(10)(11); the stress-activated enzymes HO-1 and iNOS are among the targets of the transcription factors (12)(13)(14)(15). Moreover, an outcome of ERK activation is cell differentiation and proliferation; notably, the overexpression of hBVR results in a striking change in cell morphology (16).…”

“…Target amino acid(s) of a wt cDNA clone were replaced with alanine. For the kinase-defective hBVR, V [11][12][13][14] and G 17 were replaced; for the hBVR NLS mutant, A 222 IGSTG was replaced with G 222 LKRNR; and for the NES mutant, L 176 VSLFGELSL was changed to A 176 VSVFGEVSA. The D-box mutant has I 278 LHCLGL changed to A 278 AHCAGA; the C-box mutant has P 165 replaced.…”