title: IL-27 inhibits OSM-mediated TNF-alpha and iNOS gene expression in microglia.
abstract: Elevated levels of Oncostatin M (OSM), an interleukin-6 family cytokine, have been observed in multiple sclerosis (MS), HIV-associated neurocognitive disorder (HAND), and glioblastoma (GBM); however, its effects within the CNS are not well understood. OSM regulates gene expression primarily by activating the JAK/STAT, NF-kappaB, and/or MAPK pathways, in a cell-type specific manner. In our studies, OSM induces the production of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS) from microglia in an NF-kappaB-dependent manner. This expression also partially requires the intermediate production of TNF-alpha and subsequent NF-kappaB activation via TNF-R1. We also demonstrate that OSM-induced TNF-alpha production from microglia is neurotoxic. The IL-12 family member, IL-27, suppresses OSM-mediated TNF-alpha and iNOS expression at the transcriptional level by inhibiting activation of the NF-kappaB pathway, and rescues the neurotoxicity induced by OSM-stimulated microglia. These studies are the first to demonstrate the proinflammatory effects of OSM in microglia, and also identify IL-27 as a novel inhibitor of inflammatory processes in these cells.
authors.affiliation: Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Brandi J
authors.initials: BJ
authors.lastname: Baker
authors.forename: Keun W
authors.initials: KW
authors.lastname: Park
authors.forename: Hongwei
authors.initials: H
authors.lastname: Qin
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Ma
authors.forename: Etty N
authors.initials: EN
authors.lastname: Benveniste
mesh_terms: D000818:Animals; D016923:Cell Death / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology; D007378:Interleukins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D008959:Models, Neurological; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D053683:Oncostatin M / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism; D014158:Transcription, Genetic / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: C486767:Il27 protein, mouse; D007378:Interleukins; D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; C498144:Rela protein, mouse; C506236:Tnfrsf1a protein, mouse; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D053683:Oncostatin M; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse
references.citation: J Neurosci. 2009 Feb 4;29(5):1319-30
references.pmid: 19193879
references.citation: Neurosci Res. 2006 May;55(1):87-95
references.pmid: 16529832
references.citation: J Neuroimmunol. 2008 Feb;194(1-2):123-31
references.pmid: 18083240
references.citation: J Neuroimmunol. 2009 Mar 31;208(1-2):70-9
references.pmid: 19211155
references.citation: Oncogene. 2009 Oct 22;28(42):3735-45
references.pmid: 19668231
references.citation: J Neurosci. 2006 Sep 13;26(37):9365-75
references.pmid: 16971520
references.citation: Nat Rev Neurosci. 2001 Oct;2(10):734-44
references.pmid: 11584311
references.citation: Physiol Rev. 2007 Jan;87(1):315-424
references.pmid: 17237348
references.citation: Cytokine Growth Factor Rev. 2004 Oct;15(5):379-91
references.pmid: 15450253
references.citation: FASEB J. 1995 Dec;9(15):1577-84
references.pmid: 8529837
references.citation: J Neurosci. 2002 Jul 1;22(13):5334-43
references.pmid: 12097485
references.citation: J Neuroimmune Pharmacol. 2007 Jun;2(2):140-53
references.pmid: 18040839
references.citation: J Neuroimmunol. 2002 Jul;128(1-2):31-8
references.pmid: 12098508
references.citation: Oncogene. 2003 Nov 6;22(50):8117-24
references.pmid: 14603252
references.citation: Mol Cell. 2002 Mar;9(3):625-36
references.pmid: 11931769
references.citation: Methods Mol Biol. 2000;132:365-86
references.pmid: 10547847
references.citation: Mol Cell. 1998 Apr;1(5):661-71
references.pmid: 9660950
references.citation: Immunol Rev. 2008 Dec;226:234-47
references.pmid: 19161428
references.citation: Mult Scler. 2002 Aug;8(4):284-8
references.pmid: 12166497
references.citation: J Immunol. 2006 Mar 1;176(5):2773-80
references.pmid: 16493033
references.citation: Curr Drug Targets Inflamm Allergy. 2005 Aug;4(4):471-9
references.pmid: 16101524
references.citation: J Leukoc Biol. 2007 Aug;82(2):436-47
references.pmid: 17507688
references.citation: Mol Cell Biol. 2001 Oct;21(19):6461-9
references.pmid: 11533235
references.citation: J Immunol. 1999 Apr 1;162(7):4045-52
references.pmid: 10201927
references.citation: J Biol Chem. 2009 Oct 23;284(43):29571-81
references.pmid: 19654331
references.citation: Mol Cell Biol Res Commun. 1999 May;1(2):109-16
references.pmid: 10356359
references.citation: J Biol Chem. 2008 Jul 11;283(28):19465-77
references.pmid: 18430728
references.citation: J Immunol. 2007 Sep 1;179(5):3268-75
references.pmid: 17709543
references.citation: Mol Ther. 2008 Sep;16(9):1572-9
references.pmid: 18628756
references.citation: J Biol Chem. 1994 Feb 18;269(7):4705-8
references.pmid: 7508926
references.citation: J Neurosci. 2001 Feb 15;21(4):1179-88
references.pmid: 11160388
references.citation: J Immunol. 2006 Dec 1;177(11):7761-71
references.pmid: 17114447
references.citation: J Neuroimmunol. 1995 Feb;56(2):135-41
references.pmid: 7860709
references.citation: Nat Immunol. 2006 Sep;7(9):929-36
references.pmid: 16906167
references.citation: J Neurosci. 2001 Sep 1;21(17):6480-91
references.pmid: 11517237
references.citation: J Biol Chem. 1997 Jan 10;272(2):1188-96
references.pmid: 8995420
references.citation: Immunol Lett. 2008 May 15;117(2):123-30
references.pmid: 18378322
references.citation: Cell Signal. 2006 Jan;18(1):50-61
references.pmid: 15935618
references.citation: Glia. 2008 Aug 15;56(11):1250-62
references.pmid: 18571793
references.citation: Nat Immunol. 2007 Dec;8(12):1372-9
references.pmid: 17994023
references.citation: J Cell Biol. 2007 Aug 27;178(5):829-41
references.pmid: 17724122
references.citation: J Neurosci. 2000 May 1;20(9):3456-68
references.pmid: 10777809
references.citation: J Neuropathol Exp Neurol. 2001 Nov;60(11):1087-98
references.pmid: 11706938
references.citation: Nat Rev Immunol. 2009 Jun;9(6):429-39
references.pmid: 19461673
references.citation: Nat Immunol. 2007 Dec;8(12):1363-71
references.pmid: 17994025
references.citation: Antioxid Redox Signal. 2006 May-Jun;8(5-6):929-47
references.pmid: 16771683
references.citation: J Biol Chem. 2009 Oct 23;284(43):29383-90
references.pmid: 19738286
references.citation: Nat Rev Immunol. 2003 Sep;3(9):745-56
references.pmid: 12949498
references.citation: Curr Protoc Neurosci. 2001 May;Chapter 7:Unit7.13
references.pmid: 18428524
references.citation: J Acquir Immune Defic Syndr. 2003 Apr 1;32(4):464-5
references.pmid: 12640208
references.citation: J Biol Chem. 2006 Nov 24;281(47):35785-93
references.pmid: 17005561
references.citation: J Immunol. 1998 Jan 15;160(2):943-52
references.pmid: 9551933
references.citation: J Biol Chem. 1999 Oct 1;274(40):28823-7
references.pmid: 10497256
references.citation: Brain Res. 2005 Apr 8;1040(1-2):202-7
references.pmid: 15804443
references.citation: Mol Cell Biol. 1990 Apr;10(4):1498-506
references.pmid: 2181276
references.citation: Mol Cell Biol. 2001 Oct;21(20):7065-77
references.pmid: 11564889
references.citation: Neurosci Lett. 2008 Aug 22;441(2):163-6
references.pmid: 18603369
references.citation: J Neurochem. 2001 Jul;78(1):129-40
references.pmid: 11432980
references.citation: Nat Immunol. 2007 Dec;8(12):1380-9
references.pmid: 17994022
references.citation: J Biol Chem. 2002 Apr 19;277(16):13796-803
references.pmid: 11830590
references.citation: J Immunol. 2002 Sep 1;169(5):2354-60
references.pmid: 12193701
references.citation: Nat Neurosci. 2001 Nov;4(11):1116-22
references.pmid: 11600888
references.citation: Arterioscler Thromb Vasc Biol. 2008 Mar;28(3):498-503
references.pmid: 18187666
references.citation: J Neurosci. 2009 Feb 18;29(7):2089-102
references.pmid: 19228962