title: Constitutive activation of p38 and ERK1/2 MAPKs in epithelial cells of myasthenic thymus leads to IL-6 and RANTES overexpression: effects on survival and migration of peripheral T and B cells.
abstract: Myasthenia gravis (MG) is an autoimmune disease of neuromuscular junctions where thymus plays a pathogenetic role. Thymectomy benefits patients, and thymic hyperplasia, a lymphoid infiltration of perivascular spaces becoming site of autoantibody production, is recurrently observed. Cytokines and chemokines, produced by thymic epithelium and supporting survival and migration of T and B cells, are likely to be of great relevance in pathogenesis of thymic hyperplasia. In thymic epithelial cell (TEC) cultures derived "in vitro" from normal or hyperplastic age-matched MG thymuses, we demonstrate by gene profiling analysis that MG-TEC basally overexpress genes coding for p38 and ERK1/2 MAPKs and for components of their signaling pathways. Immunoblotting experiments confirmed that p38 and ERK1/2 proteins were overexpressed in MG-TEC and, in addition, constitutively activated. Pharmacological blockage with specific inhibitors confirmed their role in the control of IL-6 and RANTES gene expression. According to our results, IL-6 and RANTES levels were abnormally augmented in MG-TEC, either basally or upon induction by adhesion-related stimuli. The finding that IL-6 and RANTES modulate, respectively, survival and migration of peripheral lymphocytes of myasthenic patients point to MAPK transcriptional and posttranscriptional abnormalities of MG-TEC as a key step in the pathological remodelling of myasthenic thymus.
authors.affiliation: Section of Immunology, Department of Pathology, University of Verona, Italy.
authors.forename: Michaela
authors.initials: M
authors.lastname: Colombara
authors.forename: Valeria
authors.initials: V
authors.lastname: Antonini
authors.forename: Anna Pia
authors.initials: AP
authors.lastname: Riviera
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Mainiero
authors.forename: Raffaele
authors.initials: R
authors.lastname: Strippoli
authors.forename: Marcello
authors.initials: M
authors.lastname: Merola
authors.forename: Giulio
authors.initials: G
authors.lastname: Fracasso
authors.forename: Ornella
authors.initials: O
authors.lastname: Poffe
authors.forename: Nadia
authors.initials: N
authors.lastname: Brutti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Tridente
authors.forename: Marco
authors.initials: M
authors.lastname: Colombatti
authors.forename: Dunia
authors.initials: D
authors.lastname: Ramarli
mesh_terms: D000293:Adolescent; D000328:Adult; D001402:B-Lymphocytes / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D016022:Case-Control Studies; D002465:Cell Movement; D002470:Cell Survival; D018946:Chemokine CCL5 / Q000096:biosynthesis*; D002648:Child; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000201:enzymology / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis*; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009157:Myasthenia Gravis / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D013950:Thymus Gland / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D018946:Chemokine CCL5; D015850:Interleukin-6; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases