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p38 MAPK is a critical regulator of the constitutive and the beta4 integrin-regulated expression of IL-6 in human normal thymic epithelial cells.
- Source :
-
European journal of immunology [Eur J Immunol] 2003 Nov; Vol. 33 (11), pp. 3038-48. - Publication Year :
- 2003
-
Abstract
- Cytokines and adhesion receptors are key mediators in the dialog occurring between thymic epithelial cells (TEC) and thymocytes and regulating T cell maturation and epithelial embryonic differentiation. Among cytokines, IL-6 can be critical in the thymus, fostering proliferation, differentiation and/or survival of both TEC and thymocytes. We have previously reported in human normal TEC that clustering of the laminin receptor alpha6beta4 integrin induced by thymocyte contact or monoclonal antibody-mediated cross-linking regulates IL-6 gene expression via activation of NF-kappaB and NF-IL6 transactivators. Here we show that alpha6beta4 integrin activates p38 mitogen-activated protein kinase (MAPK) and that p38 is essential for IL-6 gene expression. In fact, beta4 cross-linking activated p38 and extracellular signal-regulated kinase (ERK) MAPK, Rac1, p21-activated protein kinase 1 (PAK1) and MAPK kinases (MKK) 3/MKK6. However, pharmacological blockade of p38 or ERK demonstrated that p38 inhibition abrogated both basal and beta4 integrin-induced production of IL-6 preventing NF-kappaB and NF-IL6 activation, whereas ERK inhibition reduced IL-6 production, hampering only NF-kappaB activation. Overall, our results indicate that p38 MAPK and alpha6beta4 integrin, expressed by TEC throughout their life, are critical regulators of the intrathymic availability of a cytokine controlling fate and functions of cells governing development and maintenance of thymic architecture and immune responses.
- Subjects :
- CCAAT-Enhancer-Binding Protein-beta metabolism
Calcium-Calmodulin-Dependent Protein Kinases metabolism
Epithelium immunology
Epithelium metabolism
Humans
Integrin beta4 immunology
Interleukin-6 biosynthesis
Laminin metabolism
MAP Kinase Kinase 3
MAP Kinase Kinase 6
Mitogen-Activated Protein Kinase Kinases metabolism
NF-kappa B metabolism
Protein Serine-Threonine Kinases metabolism
Protein-Tyrosine Kinases metabolism
Thymus Gland immunology
p21-Activated Kinases
p38 Mitogen-Activated Protein Kinases
rac1 GTP-Binding Protein metabolism
Integrin beta4 metabolism
Interleukin-6 genetics
Mitogen-Activated Protein Kinases metabolism
Thymus Gland metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0014-2980
- Volume :
- 33
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- European journal of immunology
- Publication Type :
- Academic Journal
- Accession number :
- 14579272
- Full Text :
- https://doi.org/10.1002/eji.200323931