p38 MAPK is a critical regulator of the constitutive and the β4 integrin‐regulated expression of IL‐6 in human normal thymic epithelial cells

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 § 6 g 4 integrin induced by thymocyte contact or monoclonal antibody-mediated cross-linking regulates IL-6 gene expression via activation of NF-‹ B and NF-IL6 transactivators. Here we show that § 6 g 4 integrin activates p38 mitogen-activated protein kinase (MAPK) and that p38 is essential for IL-6 gene expression. In fact, g 4 cross-linking activated p38 and extracellular signalregulated 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 g 4 integrin-induced production of IL-6 preventing NF-‹ B and NF-IL6 activation, whereas ERK inhibition reduced IL-6 production, hampering only NF-‹ B activation. Overall, our results indicate that p38 MAPK and § 6 g 4 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.

Leptin, Insulin-Like Growth Factor-1, and Insulin-Like Growth Factor-2 Are Mitogens in ApcMin/+ but not Apc+/+ Colonic Epithelial Cell Lines

“…Furthermore, as seen in Fig. 6C, in IMCE (Apc Min/+ ) cells, p38 inhibition led to a greater reduction in the leptin-induced cell proliferation than NF-nB inhibition, and this may be due to the fact that enzymatic inhibitors of p38 block both p38 phosphorylation and p38 activation-induced NF-nB activation seen in thymic epithelial cells (29).…”

Regulation of RANTES Promoter Activation in Gastric Epithelial Cells Infected withHelicobacter pylori

“…These data are consistent with the notion that H. pylori infections result in the stimulation of transcription factors which differentially affect different promoter regions. We found that the NF-IL-6 site binds H. pylori-inducible proteins belonging to the C/EBP family of transcription factors, which are involved in the regulation of immune functions and tumorigenesis and are regulated through the MAPK and NF-B pathways (18,22,29). In fact, inhibitor experiments showed that the binding complexes of NF-IL-6 were inhibited by the p38 inhibitor and the NF-B inhibitor.…”

Deletion of tetraspanin Cd151 results in decreased pathologic angiogenesis in vivo and in vitro

“…Importantly, these in vitro functional assays recapitulate the invasion, sprouting, migration, and lumenforming steps that occur in vivo, during angiogenesis. 3,7 Laminin-binding integrins can activate PI3K-Akt, 54,55 Rac1, 56-58 Cdc42, 57,59 ERK, 12,60 p38 MAPK, 61 FAK, 60 src, 62 and Raf 63 pathways. However, only a subset of these signaling molecules (Akt, Rac1, and Cdc42) showed markedly reduced laminin-dependent activation in Cd151-null MLECs.…”