title: Inflammatory response of microglial BV-2 cells includes a glycolytic shift and is modulated by mitochondrial glucose-regulated protein 75/mortalin.
abstract: Recent studies suggest a link between mitochondria and proinflammatory cytokine generation. We previously demonstrated that overexpression of mitochondrial chaperone glucose-regulated protein75 (Grp75/mortalin) protects mitochondria. In this study we investigated the modulation of the lipopolisaccharide (LPS)-induced inflammatory response of microglial BV-2 cells by Grp75. We demonstrate that LPS-induced activation promotes significant metabolic changes suppressing mitochondrial function and increasing glycolysis. Overexpression of Grp75 attenuates the LPS-induced oxidative and metabolic responses, and suppresses proinflammatory activation, which depends on both NF-κB activation and lactate. Thus overexpression of Grp75 provides a novel strategy to modulate proinflammatory cytokine production of relevance to inflammation-associated pathologies.
authors: Department of Anesthesia, Stanford University School of Medicine, 300 Pasteur Drive, Grant Building S272, Stanford, CA 94305, United States. ludmilav@stanford.edu
authors: Ludmila A
authors: LA
authors: Voloboueva
authors: John F
authors: JF
authors: Emery
authors: Xiaoyun
authors: X
authors: Sun
authors: Rona G
authors: RG
authors: Giffard
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects; D006019:Glycolysis / Q000187:drug effects / Q000235:genetics; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D019344:Lactic Acid / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018832:Molecular Chaperones / Q000235:genetics* / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010957:Plasmids; D014162:Transfection
chemical_list: D016207:Cytokines; D018840:HSP70 Heat-Shock Proteins; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D018832:Molecular Chaperones; D016328:NF-kappa B; C018551:glucose-regulated proteins; D019344:Lactic Acid
references: Clin Cancer Res. 2009 Dec 1;15(23):7170-4
references: 19920111
references: Mol Cell Biochem. 2005 Jan;268(1-2):45-51
references: 15724436
references: Nat Immunol. 2011 Mar;12(3):222-30
references: 21151103
references: J Immunol. 2009 Feb 15;182(4):2476-84
references: 19201903
references: Mitochondrion. 2010 Aug;10(5):411-8
references: 20573557
references: J Biol Chem. 1995 Jan 27;270(4):1705-10
references: 7829505
references: Cell. 2003 Mar 7;112(5):645-57
references: 12628185
references: J Exp Med. 2011 Mar 14;208(3):519-33
references: 21282379
references: Arch Pharm Res. 2010 Oct;33(10):1539-56
references: 21052932
references: Ann N Y Acad Sci. 2002 Apr;959:199-213
references: 11976197
references: J Biol Chem. 2011 Sep 16;286(37):32542-51
references: 21778228
references: N Engl J Med. 1997 Apr 10;336(15):1066-71
references: 9091804
references: Int J Mol Med. 2004 Jan;13(1):105-9
references: 14654979
references: Free Radic Biol Med. 1994 Jun;16(6):675-84
references: 8070670
references: Exp Eye Res. 2003 Jun;76(6):715-23
references: 12742354
references: J Cereb Blood Flow Metab. 2009 Feb;29(2):365-74
references: 18985056
references: Cell Metab. 2006 Jul;4(1):13-24
references: 16814729
references: J Neurol. 2004 Mar;251(3):261-8
references: 15015004
references: FEBS Lett. 2011 Jul 21;585(14):2263-8
references: 21627971
references: N Engl J Med. 2003 Jun 26;348(26):2656-68
references: 12826641
references: Am J Physiol Endocrinol Metab. 2005 Oct;289(4):E534-42
references: 15941782
references: Naunyn Schmiedebergs Arch Pharmacol. 1999 Apr;359(4):249-55
references: 10344522
references: Biochim Biophys Acta. 2000 Aug 15;1459(2-3):397-404
references: 11004456
references: J Biol Chem. 2001 Feb 16;276(7):4588-96
references: 11092892
references: Nature. 2011 Jan 13;469(7329):221-5
references: 21124315
references: J Exp Med. 2011 Mar 14;208(3):417-20
references: 21357740
references: J Neurosci Res. 1995 Apr 15;40(6):807-19
references: 7629893
references: J Cereb Blood Flow Metab. 2008 May;28(5):1009-16
references: 18091755
references: Clin Exp Immunol. 2008 Jun;152(3):415-22
references: 18422737