Amrani Y, Ammit A J, Panettieri R A
Department of Medicine, Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania 19104-6160, USA.
Mol Pharmacol. 2001 Oct;60(4):646-55.
Little information is available regarding the mechanisms involved in cytokine-induced synthetic function of human airway smooth muscle (ASM) cells. Here, we report that tumor necrosis factor receptor (TNFR) 1-induced p38 and p42/44 mitogen-activated protein kinase (MAPK) activation modulates tumor necrosis factor-alpha (TNF alpha)-mediated synthetic responses: expression of intercellular adhesion molecule-1 (ICAM-1) and secretion of interleukin (IL)-6 and the regulated-on-activation, normal T-cell expressed and secreted (RANTES) chemokine in human ASM cells. Pretreatment of ASM cells with SB203580, a p38 MAPK inhibitor, slightly enhanced TNF alpha-induced ICAM-1 expression in a dose-dependent manner but partially inhibited secretion of RANTES and IL-6. In contrast, PD98059, a p42/44 inhibitor, reduced ICAM-1 expression by 50% but had no effect on TNF alpha-induced RANTES or IL-6 secretion. SB203580 and PD98059 had little effect on TNF alpha-induced nuclear factor-kappa B (NF-kappa B) activation as determined in cells transfected with a NF-kappa B-luciferase reporter construct. We also found that agonistic antibodies specific for either TNFR1 or TNFR2 stimulated IL-6 and RANTES secretion and activated p38 and p42/44 MAPKs. In addition, both antibodies induced NF-kappa B-mediated gene transcription. Using receptor-specific blocking antibodies, we found that TNFR1 primarily regulates TNF alpha-induced IL-6 and RANTES secretion and activation of p38 and p42/44 MAPK pathways. Interestingly, we found that TNFR1 and TNFR2 are expressed differently on the cell surface of ASM cells. Our data suggest that despite the presence of functional TNFR2, TNFR1 associated with MAPK-dependent and -independent pathways is the primary signaling pathway involved in TNF alpha-induced synthetic functions in ASM cells.
关于细胞因子诱导人气道平滑肌（ASM）细胞合成功能的相关机制，目前所知甚少。在此，我们报告肿瘤坏死因子受体（TNFR）1诱导的p38和p42/44丝裂原活化蛋白激酶（MAPK）激活调节肿瘤坏死因子-α（TNFα）介导的合成反应：人ASM细胞中细胞间黏附分子-1（ICAM-1）的表达、白细胞介素（IL）-6的分泌以及激活调节正常T细胞表达和分泌（RANTES）趋化因子。用p38 MAPK抑制剂SB203580预处理ASM细胞，以剂量依赖方式轻微增强TNFα诱导的ICAM-1表达，但部分抑制RANTES和IL-6的分泌。相比之下，p42/44抑制剂PD98059使ICAM-1表达降低50%，但对TNFα诱导的RANTES或IL-6分泌无影响。如在转染了NF-κB荧光素酶报告构建体的细胞中所测定的，SB203580和PD98059对TNFα诱导的核因子-κB（NF-κB）激活影响很小。我们还发现，针对TNFR1或TNFR2的激动性抗体刺激IL-6和RANTES分泌并激活p38和p42/44 MAPK。此外，两种抗体均诱导NF-κB介导的基因转录。使用受体特异性阻断抗体，我们发现TNFR1主要调节TNFα诱导的IL-6和RANTES分泌以及p38和p42/44 MAPK途径的激活。有趣的是，我们发现TNFR1和TNFR2在ASM细胞表面的表达不同。我们的数据表明，尽管存在功能性TNFR2，但与MAPK依赖性和非依赖性途径相关的TNFR1是参与TNFα诱导ASM细胞合成功能的主要信号通路。
