1. Biliverdin modulates the expression of C5aR in response to endotoxin in part via mTOR signaling
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Kavita Bisht, Oliver Neubauer, Andrew C. Bulmer, Barbara Wegiel, Karl-Heinz Wagner, Jens Tampe, and Leo E. Otterbein
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Lipopolysaccharides ,Macrophage ,GAPDH, glyceraldehyde 3-phosphate dehydrogenase ,Complement receptor ,030204 cardiovascular system & hematology ,Biochemistry ,Antioxidants ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,FACS, fluorescence-activated cell sorting ,polycyclic compounds ,ANOVA, analysis of variance ,NF-κB, nuclear factor kappa B ,0303 health sciences ,TOR Serine-Threonine Kinases ,Cell biology ,mTOR ,lipids (amino acids, peptides, and proteins) ,Signal transduction ,medicine.symptom ,Signal Transduction ,Bilirubin ,Biophysics ,Inflammation ,Biology ,Article ,Cell Line ,03 medical and health sciences ,medicine ,Animals ,Protein kinase B ,Receptor, Anaphylatoxin C5a ,Molecular Biology ,PI3K/AKT/mTOR pathway ,030304 developmental biology ,Biliverdin ,qRT-PCR, quantitative real time polymerase chain reaction ,Macrophages ,Biliverdine ,NF-κB ,Cell Biology ,Macrophage Activation ,BCA, bicinchoninic acid ,Endotoxins ,chemistry ,M-CSF, macrophage-colony stimulating factor ,HPRT, hypoxanthine-guanine phosphoribosyltransferase - Abstract
Highlights • Biliverdin mitigates LPS-dependent C5aR expression in macrophages in part via mTOR. • Biliverdin promotes phosphorylation of Akt and PS6. • Biliverdin decreases LPS-mediated induction of C5aR-associated cytokines., 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.
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