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J. Biol. Chem. 284 (32): 21369-21378

© 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

Cell Surface Biliverdin Reductase Mediates Biliverdin-induced Anti-inflammatory Effects via Phosphatidylinositol 3-Kinase and Akt*Formula

Barbara Wegiel{ddagger}, Catherine J. Baty§, David Gallo{ddagger}, Eva Csizmadia{ddagger}, Jeffrey R. Scott{ddagger}, Ardavan Akhavan, Beek Y. Chin{ddagger}, Elzbieta Kaczmarek{ddagger}, Jawed Alam||, Fritz H. Bach{ddagger}, Brian S. Zuckerbraun, , and Leo E. Otterbein{ddagger}1

From the {ddagger}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 Back to Top

Abstract: 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 p85{alpha} 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.


Abbreviations: BVR, biliverdin reductase • DMSO, dimethyl sulfoxide • LPS, lipopolysaccharide • PI3K, phosphatidylinositol 3-kinase • IL, interleukin • HEK, human embryonic kidney • PBS, phosphate-buffered saline • siRNA, small interfering RNA • RNAi, interfering RNA • Ad, adenovirus • TIRF, total internal reflective fluorescence • BSA, bovine serum albumin • FITC, fluorescein isothiocyanate • BisTris, 2-[bis(2-hydroxyethyl)amino]-2-(hydroxymethyl)propane-1,3-diol • MES, 4-morpholineethanesulfonic acid • ELISA, enzyme-linked immunosorbent assay • FACS, fluorescence-activated cell sorter • BR, bilirubin • WT, wild type.

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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