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Cell Surface Biliverdin Reductase Mediates Biliverdin-induced Anti-inflammatory Effects via Phosphatidylinositol 3-Kinase and Akt*
Barbara Wegiel,
Catherine J. Baty,
David Gallo,
Eva Csizmadia,
Jeffrey R. Scott,
Ardavan Akhavan¶,
Beek Y. Chin,
Elzbieta Kaczmarek,
Jawed Alam||,
Fritz H. Bach,
Brian S. Zuckerbraun¶, , and
Leo E. Otterbein1
From the Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215,
the Departments of Cell Biology and ¶Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, and
the ||Department of Molecular Genetics, Alton Ochsner Foundation, and Department of Biochemistry and Molecular Biology, Louisiana State University, New Orleans, Louisiana 70112
Abstract:
Biliverdin reductase A (BVR) catalyzes the reduction of biliverdin(BV) to bilirubin (BR) in all cells. Others and we have shownthat 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 thatBVR is expressed on the external plasma membrane of macrophages(and other cells) where it quickly converts BV to BR. The enzymaticconversion of BV to BR on the surface by BVR initiates a signalingcascade through tyrosine phosphorylation of BVR on the cytoplasmictail. Phosphorylated BVR in turn binds to the p85 subunit ofphosphatidylinositol 3-kinase and activates downstream signalingto Akt. Using bacterial endotoxin (lipopolysaccharide) to initiatean inflammatory response in macrophages, we find a rapid increasein BVR surface expression. One of the mechanisms by which BVmediates its protective effects in response to lipopolysaccharideis through enhanced production of interleukin-10 (IL-10) theprototypical anti-inflammatory cytokine. IL-10 regulation isdependent in part on the activation of Akt. The effects of BVon IL-10 expression are lost with blockade of Akt. Inhibitionof surface BVR with RNA interference attenuates BV-induced Aktsignaling and IL-10 expression and in vivo negates the cytoprotectiveeffects of BV in models of shock and acute hepatitis. Collectively,our findings elucidate a potentially important new molecularmechanism by which BV, through the enzymatic activity and phosphorylationof surface BVR (BVR)surf modulates the inflammatory response.
Received for publication March 18, 2009.
Revision received May 29, 2009.
1 To whom correspondence should be addressed: 3 Blackfan Circle, Rm. 624, Boston, MA 02215. Fax: 617-735-2844; E-mail: lotterbe{at}bidmc.harvard.edu.
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[DOI: 10.1126/scisignal.283ec266] |Abstract »
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,
Catherine J. Baty
,
David Gallo
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. 
