Cell surface biliverdin reductase mediates biliverdin-induced anti-inflammatory effects via phosphatidylinositol 3-kinase and Akt
Authors: Barbara Wegiel
Eva Csizmadia
Jawed Alam
David Gallo
Leo E Otterbein
Jeffrey R Scott
Brian S Zuckerbraun
Ardavan Akhavan
Catherine J Baty
Elzbieta Kaczmarek
Fritz H Bach
Beek Y Chin
Journal: Journal of Biological Chemistry (2009)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Biliverdin reductase A; BV; BR; anti-inflammatory; macrophages
Affiliations: Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.

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 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. 

Retracted: No

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 Via https: www.ilfattoquotidiano.it in-edicola articoli 2019 11 28 ricerche-mediche-aggiustate-pero-la-scienza-tace 5583974 (and Google translate) Fixed medical research, but science is silent by Gianni Barbacetto | NOVEMBER 28, 2019 u201cFor justice everything is fine. But is this okay for the scientific community ? Is it possible to falsify the images of the experiments, or avoid doing the control experiment, without anyone having anything to say? These are the questions that remain, at the end of a long judicial investigation by the Milan Public Prosecutor s Office on some articles of the most important Italian scientists engaged in cancer research. Professor Alberto Mantovani of Humanitas, Pier Giuseppe Pelicci of Ieo, Pier Paolo Di Fiore of Ifom, Marco Pierotti, with Maria Angela Greco, Elena Tamburini and Silvana Pilotti of the Cancer Institute, were investigated by prosecutors Francesco Cajani and Paolo Filippini for having manipulated the images of some of their studies published in international scientific journals. They are research luminaries who maneuver millions of euros from public funds, private donations, 5 per thousand collections . They received, only in the period analyzed by the Public Prosecutor (2005-2012), very high figures: 9.37 million Di Fiore; 3.06 Mantovani; 1.48 Pelicci; 3.60 Pierotti, for a total of 17 million paid by the CNR , the Ministry of Health and the University. And they got caught  fixing their research records. Now the judge of the preliminary investigation Sofia Fioretta has closed the investigation started in 2014, dismissing the accusations and arguing - with bold arguments - that the professors  did not carry out any falsification activities  . The two prosecutors had already requested the filing, arguing that the manipulations are established, but that the crime of  scientific fraud does not exist in Italy (as there is instead that of insurance fraud and sports fraud), therefore it is not possible pursue the behaviors of the seven excellent oncologists. The investigating judge was more creative : he recognized  a harmless and innocent fake , realized  because there was no time or money to perform the replication, or because competitors were coming first (what stupid scientists who do everything right instead ). Therefore,  insignificant errors were made . Replicas of the experiments were not carried out, but this  did not affect the content of the research and  did not undermine the scientific validity of the published thesis . In short: the luminaries were wrong, but in modest quantity . Yet the examinations of the experts of the Public Prosecutor s Office have ascertained the manipulations: three in the works of Pelicci-Ieo, four in those of the group of Pierotti-Istituto dei tumori (i.e. two by Pilotti and one by Greco and Tamburini), one in the works by Di Fiore-Ifom and one by Mantovani-Humanitas. But nothing wrong with that, that s okay, the investigating judge Fioretta reassures us. Closed the judicial game, at this point we ask some questions to the scientific community: 1. Are there, in scientific practice,  harmless and innocent false manipulations , but  of little significance ? 2. Is it normal that seven luminaries of oncology research publish images in international scientific journals that are manipulated in 21 out of 27 cases analyzed? 3. Is it compatible with the scientific method that, having performed the first experiment, one tarot the replica,  because there was no time or money to perform it,  or because competitors were arriving first ? 4. Since it is impossible, on the judicial level, to establish the direct connection between research carried out and funds obtained, is it still normal, on the scientific and ethical level, to obtain money, public and private, with the prestige gained (also) with fake research? 5. Is the scientific community sure that squaring up (corporately) and rejoicing in the  false innocents is the best way to defend science and the scientific method, now threatened by charlatans, scoundrels and no-vaxes?u201d ,