title: IL-6 and Akt are involved in muscular pathogenesis in myasthenia gravis.
abstract: BACKGROUND
  Anti-acetylcholine receptor (AChR) autoantibodies target muscles in spontaneous human myasthenia gravis (MG) and its induced experimental autoimmune model MG (EAMG). The aim of this study was to identify novel functional mechanisms occurring in the muscle pathology of myasthenia.
  
  
  RESULTS
  A transcriptome analysis performed on muscle tissue from MG patients (compared with healthy controls) and from EAMG rats (compared with control rats) revealed a deregulation of genes associated with the Interleukin-6 (IL-6) and Insulin-Like Growth Factor 1 (IGF-1) pathways in both humans and rats. The expression of IL-6 and its receptor IL-6R transcripts was found to be altered in muscles of EAMG rats and mice compared with control animals. In muscle biopsies from MG patients, IL-6 protein level was higher than in control muscles. Using cultures of human muscle cells, we evaluated the effects of anti-AChR antibodies on IL-6 production and on the phosphorylation of Protein Kinase B (PKB/Akt). Most MG sera and some monoclonal anti-AChR antibodies induced a significant increase in IL-6 production by human muscle cells. Furthermore, Akt phosphorylation in response to insulin was decreased in the presence of monoclonal anti-AChR antibodies.
  
  
  CONCLUSIONS
  Anti-AChR antibodies alter IL-6 production by muscle cells, suggesting a putative novel functional mechanism of action for the anti-AChR antibodies. IL-6 is a myokine with known effects on signaling pathways such as Akt/mTOR (mammalian Target of Rapamycin). Since Akt plays a key role in multiple cellular processes, the reduced phosphorylation of Akt by the anti-AChR antibodies may have a significant impact on the muscle fatigability observed in MG patients.
authors: Marie
authors: M
authors: Maurer
authors: Sylvain
authors: S
authors: Bougoin
authors: Tali
authors: T
authors: Feferman
authors: Mélinée
authors: M
authors: Frenkian
authors: Jacky
authors: J
authors: Bismuth
authors: Vincent
authors: V
authors: Mouly
authors: Geraldine
authors: G
authors: Clairac
authors: Socrates
authors: S
authors: Tzartos
authors: Elie
authors: E
authors: Fadel
authors: Bruno
authors: B
authors: Eymard
authors: Sara
authors: S
authors: Fuchs
authors: Miriam C
authors: MC
authors: Souroujon
authors: Sorbonne Universités, UPMC Univ Paris 06, Myology Research Center UM76, Paris, F-75013, France. sonia.berrih-aknin@upmc.fr.
authors: Sonia
authors: S
authors: Berrih-Aknin
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002648:Child; D004195:Disease Models, Animal; D005260:Female; D005620:Freund's Adjuvant / Q000633:toxicity; D020869:Gene Expression Profiling; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism*; D009157:Myasthenia Gravis / Q000209:etiology / Q000235:genetics / Q000473:pathology*; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D011950:Receptors, Cholinergic / Q000276:immunology; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D055815:Young Adult
chemical_list: D000906:Antibodies; D015850:Interleukin-6; D011950:Receptors, Cholinergic; D019947:Receptors, Interleukin-6; D007334:Insulin-Like Growth Factor I; D005620:Freund's Adjuvant; D051057:Proto-Oncogene Proteins c-akt
references: Biochem Biophys Res Commun. 1995 Nov 2;216(1):49-53
references: 7488123
references: Cytokine. 2006 Jul;35(1-2):100-6
references: 16919469
references: Ann N Y Acad Sci. 1996 Feb 13;778:258-72
references: 8610979
references: Int Rev Immunol. 1997;15(1-2):101-27
references: 9178074
references: J Clin Invest. 1998 Jul 1;102(1):249-63
references: 9649579
references: Blood. 2006 Jul 15;108(2):432-40
references: 16543475
references: Exp Physiol. 2013 Feb;98(2):359-71
references: 22941979
references: Mol Cell Biol. 2006 Nov;26(22):8228-41
references: 16954375
references: J Immunol. 2006 Dec 1;177(11):7868-79
references: 17114458
references: Aging Cell. 2007 Aug;6(4):515-23
references: 17559502
references: Ann Neurol. 2000 Nov;48(5):696-705
references: 11079532
references: Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5116-21
references: 11309499
references: Toxicol Sci. 2002 Jul;68(1):93-101
references: 12075114
references: J Immunol. 2002 Jul 15;169(2):1077-83
references: 12097416
references: Circulation. 2003 Jan 21;107(2):320-5
references: 12538435
references: Am J Physiol Regul Integr Comp Physiol. 2003 May;284(5):R1249-54
references: 12676746
references: Biochem Biophys Res Commun. 2003 Oct 17;310(2):550-4
references: 14521945
references: Exerc Immunol Rev. 2003;9:40-7
references: 14686093
references: BMC Bioinformatics. 2004 Feb 18;5:16
references: 14975175
references: Immunochemistry. 1977 Feb;14(2):129-37
references: 67081
references: Trans Am Neurol Assoc. 1977;102:96-100
references: 616125
references: Adv Cytopharmacol. 1979;3:279-85
references: 382790
references: Ann N Y Acad Sci. 1987;505:526-38
references: 3479935
references: FEBS Lett. 1988 Jun 20;233(2):277-81
references: 3260196
references: J Neurol Sci. 1992 Oct;112(1-2):185-91
references: 1469431
references: J Immunol. 1993 Dec 1;151(11):6442-50
references: 8245477
references: J Clin Invest. 1994 Jul;94(1):16-24
references: 8040257
references: Biochem Biophys Res Commun. 1995 Feb 6;207(1):168-74
references: 7857261
references: Immunol Rev. 1998 Jun;163:89-120
references: 9700504
references: Toxicol Pathol. 2005;33(1):136-45
references: 15805065
references: J Immunol. 2005 May 1;174(9):5324-31
references: 15843529
references: J Immunol. 2005 May 15;174(10):5941-9
references: 15879086
references: Expert Opin Biol Ther. 2005 Jul;5(7):983-95
references: 16018742
references: J Immunol. 2005 Aug 1;175(3):2018-25
references: 16034147
references: Ann Rheum Dis. 2005 Sep;64(9):1257-62
references: 15731288
references: J Biol Chem. 2006 Mar 17;281(11):7060-7
references: 16418171
references: Brain. 2008 Jul;131(Pt 7):1940-52
references: 18515870
references: J Neuroimmunol. 2008 Sep 15;201-202:57-63
references: 18691767
references: Diabetes. 2008 Dec;57(12):3211-21
references: 18796617
references: Neuropathol Appl Neurobiol. 2009 Feb;35(1):103-10
references: 19187062
references: J Neuroimmunol. 2009 Apr 30;209(1-2):87-95
references: 19232748
references: Trends Endocrinol Metab. 2009 Sep;20(7):349-56
references: 19729319
references: Ann Neurol. 2009 Oct;66(4):521-31
references: 19847900
references: J Cell Mol Med. 2009 Aug;13(8B):2008-18
references: 18657229
references: Annu Rev Immunol. 2010;28:535-71
references: 20192809
references: Autoimmunity. 2010 Aug;43(5-6):353-70
references: 20380584
references: Immunol Lett. 2010 Oct 30;133(2):55-61
references: 20708640
references: J Autoimmun. 2011 Mar;36(2):135-41
references: 21193288
references: J Cell Biochem. 2012 Mar;113(3):923-33
references: 22033984
references: J Clin Invest. 1996 Jan 1;97(1):244-9
references: 8550842