p38 MAPK is a critical regulator of the constitutive and the β4 integrin-regulated expression of IL-6 in human normal thymic epithelial cells
✍ Scribed by Fabrizio Mainiero; Michaela Colombara; Valeria Antonini; Raffaele Strippoli; Marcello Merola; Ornella Poffe; Giuseppe Tridente; Dunia Ramarli
- Publisher
- John Wiley and Sons
- Year
- 2003
- Tongue
- English
- Weight
- 279 KB
- Volume
- 33
- Category
- Article
- ISSN
- 0014-2980
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✦ Synopsis
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 α6β4 integrin induced by thymocyte contact or monoclonal antibody‐mediated cross‐linking regulates IL‐6 gene expression via activation of NF‐κB and NF‐IL6 transactivators. Here we show that α6β4 integrin activates p38 mitogen‐activated protein kinase (MAPK) and that p38 is essential for IL‐6 gene expression. In fact, β4 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 β4 integrin‐induced production of IL‐6 preventing NF‐κB and NF‐IL6 activation, whereas ERK inhibition reduced IL‐6 production, hampering only NF‐κB activation. Overall, our results indicate that p38 MAPK and α6β4 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.