Cell surface biliverdin reductase mediates biliverdin-induced anti-inflammatory effects via phosphatidylinositol 3-kinase and Akt.
Biliverdin reductase A (BVR) catalyzes the reduction of biliverdin (BV) to bilirubin (BR) in all cells. Others and we have shown that biliverdin is a potent anti-inflammatory molecule, however, the mechanism by which BV exerts its protective effects is unclear. We describe and elucidate a novel finding demonstrating that BVR is expressed on the external plasma membrane of macrophages (and other cells) where it quickly converts BV to BR. The enzymatic conversion of BV to BR on the surface by BVR initiates a signaling cascade through tyrosine phosphorylation of BVR on the cytoplasmic tail. Phosphorylated BVR in turn binds to the p85alpha subunit of phosphatidylinositol 3-kinase and activates downstream signaling to Akt. Using bacterial endotoxin (lipopolysaccharide) to initiate an inflammatory response in macrophages, we find a rapid increase in BVR surface expression. One of the mechanisms by which BV mediates its protective effects in response to lipopolysaccharide is through enhanced production of interleukin-10 (IL-10) the prototypical anti-inflammatory cytokine. IL-10 regulation is dependent in part on the activation of Akt. The effects of BV on IL-10 expression are lost with blockade of Akt. Inhibition of surface BVR with RNA interference attenuates BV-induced Akt signaling and IL-10 expression and in vivo negates the cytoprotective effects of BV in models of shock and acute hepatitis. Collectively, our findings elucidate a potentially important new molecular mechanism by which BV, through the enzymatic activity and phosphorylation of surface BVR (BVR)(surf) modulates the inflammatory response.
Wegiel
Barbara
B
Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Baty
Catherine J
CJ
Gallo
David
D
Csizmadia
Eva
E
Scott
Jeffrey R
JR
Akhavan
Ardavan
A
Chin
Beek Y
BY
Kaczmarek
Elzbieta
E
Alam
Jawed
J
Bach
Fritz H
FH
Zuckerbraun
Brian S
BS
Otterbein
Leo E
LE
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001664:Biliverdine / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D016753:Interleukin-10 / Q000096:biosynthesis / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000096:biosynthesis / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D016753:Interleukin-10; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D001664:Biliverdine