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

Abstract

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.