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‐κB 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‐κB activation and the converse effect of hBVR. Biliverdin, in a concentration‐ and time‐dependent manner, inhibited transcriptional activity of NF‐κB in HEK293A cells. Nuclear extracts from biliverdin‐treated cells show reduced DNA binding of NF‐κB in an electromobility shift assay, whereas extracts from cells treated with TNF‐α showed enhanced binding. Coimmunoprecipitation data show hBVR binds to the 65 kDa subunit of NF‐κB, and that this is dependent on activation by TNF‐α. Overexpression of hBVR enhanced both the basal and TNF‐α‐mediated activation of NF‐κB and also that of the NF‐κB‐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‐κB 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‐κB might be augmented. © 2007 Wiley‐Liss, Inc.