title: Biliverdin modulates the expression of C5aR in response to endotoxin in part via mTOR signaling.
abstract: Macrophages play a crucial role in the maintenance and resolution of inflammation and express a number of pro- and anti-inflammatory molecules in response to stressors. Among them, the complement receptor 5a (C5aR) plays an integral role in the development of inflammatory disorders. Biliverdin and bilirubin, products of heme catabolism, exert anti-inflammatory effects and inhibit complement activation. Here, we define the effects of biliverdin on C5aR expression in macrophages and the roles of Akt and mammalian target of rapamycin (mTOR) in these responses. Biliverdin administration inhibited lipopolysaccharide (LPS)-induced C5aR expression (without altering basal expression), an effect partially blocked by rapamycin, an inhibitor of mTOR signaling. Biliverdin also reduced LPS-dependent expression of the pro-inflammatory cytokines TNF-α and IL-6. Collectively, these data indicate that biliverdin regulates LPS-mediated expression of C5aR via the mTOR pathway, revealing an additional mechanism underlying biliverdin's anti-inflammatory effects.
authors.affiliation: Heart Foundation Research Center, Griffith Health Institute, Griffith University, Gold Coast, Australia; Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA.
authors.forename: Kavita
authors.initials: K
authors.lastname: Bisht
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Wegiel
authors.affiliation: Griffith Enterprise, Griffith University, Nathan, Australia.
authors.forename: Jens
authors.initials: J
authors.lastname: Tampe
authors.affiliation: Emerging Field Oxidative Stress and DNA Stability and Research Platform Active Aging, Department of Nutritional Science, University of Vienna, Vienna, Austria.
authors.forename: Oliver
authors.initials: O
authors.lastname: Neubauer
authors.affiliation: Emerging Field Oxidative Stress and DNA Stability and Research Platform Active Aging, Department of Nutritional Science, University of Vienna, Vienna, Austria.
authors.forename: Karl-Heinz
authors.initials: KH
authors.lastname: Wagner
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, USA.
authors.forename: Leo E
authors.initials: LE
authors.lastname: Otterbein
authors.affiliation: Heart Foundation Research Center, Griffith Health Institute, Griffith University, Gold Coast, Australia. Electronic address: a.bulmer@griffith.edu.au.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Bulmer
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001664:Biliverdine / Q000494:pharmacology*; D002460:Cell Line; D004731:Endotoxins / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects / Q000502:physiology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D044087:Receptor, Anaphylatoxin C5a / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D004731:Endotoxins; D008070:Lipopolysaccharides; D044087:Receptor, Anaphylatoxin C5a; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D001664:Biliverdine
keywords: Inflammation; Macrophage; mTOR