1. 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.
- Author
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Colombara M, Antonini V, Riviera AP, Mainiero F, Strippoli R, Merola M, Fracasso G, Poffe O, Brutti N, Tridente G, Colombatti M, and Ramarli D
- Subjects
- Adolescent, Adult, B-Lymphocytes pathology, Case-Control Studies, Cell Movement, Cell Survival, Child, Enzyme Activation, Epithelial Cells enzymology, Epithelial Cells immunology, Extracellular Signal-Regulated MAP Kinases genetics, Female, Gene Expression, Humans, MAP Kinase Signaling System, Male, Middle Aged, Mitogen-Activated Protein Kinase 1 genetics, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 genetics, Mitogen-Activated Protein Kinase 3 metabolism, Myasthenia Gravis pathology, T-Lymphocytes pathology, Thymus Gland enzymology, Thymus Gland immunology, Thymus Gland pathology, p38 Mitogen-Activated Protein Kinases genetics, p38 Mitogen-Activated Protein Kinases metabolism, B-Lymphocytes enzymology, B-Lymphocytes immunology, Chemokine CCL5 biosynthesis, Extracellular Signal-Regulated MAP Kinases metabolism, Interleukin-6 biosynthesis, Myasthenia Gravis enzymology, Myasthenia Gravis immunology, T-Lymphocytes enzymology, T-Lymphocytes immunology
- 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.
- Published
- 2005
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