Tat-biliverdin reductase A inhibits inflammatory response by regulation of MAPK and NF-κB pathways in Raw 264.7 cells and edema mouse model

• Transduced Tat-BLVRA protects against LPS-induced macrophage cell damage.
• Tat-BLVRA inhibits cellular ROS levels and DNA fragmentation.
• Tat-BLVRA inhibits MAPKs and NF-κB activation.
• Tat-BLVRA significantly ameliorates inflammation response in vitro and in vivo.
• Tat-BLVRA can be a therapeutic agent for inflammation.

Reactive oxygen species (ROS) accumulation induces oxidative stress and cell damage, which then activates several signaling pathways and triggers inflammatory response. Biliverdin is a natural product of heme metabolism which is converted to bilirubin by the enzyme biliverdin reductase A (BLVRA) which also plays a role in antioxidant activity via the ROS scavenging activity of bilirubin. In this study, we examined the anti-inflammatory and anti-apoptotic effects of Tat-BLVRA protein on lipopolysaccharide (LPS)-induced inflammation in Raw 264.7 macrophage cells. Transduction of Tat-BLVRA protein into Raw 264.7 cells and mice ear tissue was tested by Western blot analysis and immunohistochemical analysis. Tat-BLVRA protein was effective in inhibiting mitogen activated protein kinases (MAPKs), Akt and NF-κB activation, intracellular ROS production and DNA fragmentation. Also, Tat-BLVRA protein significantly inhibited the expression of cytokines, COX-2, and iNOS. In a 12-O-tetradecanoylphobol 13-acetate (TPA)-induced mouse model, mice ears treated with Tat-BLVRA protein showed decreased ear thickness and weight, as well as inhibited MAPKs activation and cytokine expression. Thus we suggested that Tat-BLVRA protein may provide an effective therapeutic agent for inflammatory skin diseases.