Effects of cytokines on acetylcholine receptor expression: implications for myasthenia gravis.
Myasthenia gravis is an autoimmune disease associated with thymic pathologies, including hyperplasia. In this study, we investigated the processes that may lead to thymic overexpression of the triggering Ag, the acetylcholine receptor (AChR). Using microarray technology, we found that IFN-regulated genes are more highly expressed in these pathological thymic tissues compared with age- and sex-matched normal thymus controls. Therefore, we investigated whether proinflammatory cytokines could locally modify AChR expression in myoid and thymic epithelial cells. We found that AChR transcripts are up-regulated by IFN-gamma, and even more so by IFN-gamma and TNF-alpha, as assessed by real-time RT-PCR, with the alpha-AChR subunit being the most sensitive to this regulation. The expression of AChR protein was increased at the cytoplasmic level in thymic epithelial cells and at the membrane in myoid cells. To examine whether IFN-gamma could influence AChR expression in vivo, we analyzed AChR transcripts in IFN-gamma gene knock-out mice, and found a significant decrease in AChR transcript levels in the thymus but not in the muscle, compared with wild-type mice. However, up-regulation of AChR protein expression was found in the muscles of animals with myasthenic symptoms treated with TNF-alpha. Altogether, these results indicate that proinflammatory cytokines influence the expression of AChR in vitro and in vivo. Because proinflammatory cytokine activity is evidenced in the thymus of myasthenia gravis patients, it could influence AChR expression and thereby contribute to the initiation of the autoimmune anti-AChR response.
Poëa-Guyon
Sandrine
S
Unité Mixte de Recherche 8078, Centre National de la Recherche Scientifique/Université Paris Sod, Institut Paris Sod Cytokines, Hôpital Marie Lannelongue, Le Plessis-Robinson, France.
Christadoss
Premkumar
P
Le Panse
Rozen
R
Guyon
Thierry
T
De Baets
Marc
M
Wakkach
Abdelilah
A
Bidault
Jocelyne
J
Tzartos
Socrates
S
Berrih-Aknin
Sonia
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001483:Base Sequence; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology*; D006801:Humans; D006965:Hyperplasia; D018836:Inflammation Mediators / Q000502:physiology; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009157:Myasthenia Gravis / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D021122:Protein Subunits / Q000235:genetics / Q000302:isolation & purification; D051381:Rats; D011917:Rats, Inbred Lew; D011950:Receptors, Cholinergic / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification; D017471:Receptors, Interferon / Q000235:genetics; D011978:Receptors, Nicotinic / Q000096:biosynthesis; D020218:Response Elements / Q000235:genetics; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D000096743:Interferon gamma Receptor
D000911:Antibodies, Monoclonal; D016207:Cytokines; D018836:Inflammation Mediators; D007371:Interferon-gamma; D021122:Protein Subunits; D011950:Receptors, Cholinergic; D017471:Receptors, Interferon; D011978:Receptors, Nicotinic; D000096743:Interferon gamma Receptor