p38 MAPK is a critical regulator of the constitutive and the β4 integrin-regulated expression of IL-6 in human normal thymic epithelial cells
p38 MAPK is a critical regulator of the constitutive and the β4 integrin-regulated expression of IL-6 in human normal thymic epithelial cells
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DOI：
10.1002/eji.200323931
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发表时间：
2003-11-01
影响因子：
5.4
通讯作者：
Ramarli, D
中科院分区：
文献类型：
--
作者：
Mainiero, F;Colombara, M;Ramarli, D
细胞因子和粘附受体是胸腺上皮细胞（TEC）和胸腺细胞之间发生对话并调节T细胞成熟和上皮胚胎分化的关键介质。在细胞因子中，IL-6可能对胸腺至关重要，促进TEC和胸腺细胞的增殖、分化和/或存活。我们之前报道过，在人类正常TEC中，胸腺细胞接触或单克隆抗体介导的交联诱导层粘连蛋白受体α 6β 4整合素聚集，通过激活NF-kappaB和nf - IL-6反激活因子调节IL-6基因表达。本研究表明，alpha6beta4整合素可激活p38丝裂原活化蛋白激酶（MAPK），而p38对于IL-6基因表达至关重要。事实上，β 4交联激活了p38和细胞外信号调节激酶（ERK） MAPK、Rac1、p21活化蛋白激酶1 （PAK1）和MAPK激酶（MKK） 3/MKK6。然而，p38或ERK的药物阻断表明，p38抑制抑制了基础和β 4整合素诱导的IL-6的产生，阻止了NF-kappaB和NF-IL6的激活，而ERK抑制减少了IL-6的产生，仅阻碍了NF-kappaB的激活。总的来说，我们的研究结果表明，p38 MAPK和alpha6beta4整合素在TEC的整个生命周期中表达，是胸腺内细胞因子可用性的关键调节因子，控制胸腺结构和免疫反应的发育和维持的细胞的命运和功能。
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 anti body-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.