Differential roles of extracellular signal-regulated kinase-1/2 and p38MAPK in interleukin-1β- and tumor necrosis factor-α-induced low density lipoprotein receptor expression in HepG2 cells
Differential roles of extracellular signal-regulated kinase-1/2 and p38MAPK in interleukin-1β- and tumor necrosis factor-α-induced low density lipoprotein receptor expression in HepG2 cells
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DOI：
10.1074/jbc.273.25.15742
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发表时间：
1998-06-19
影响因子：
4.8
通讯作者：
Mehta, KD
中科院分区：
文献类型：
--
作者：
Kumar, A;Middleton, A;Mehta, KD
在炎性、恶性和感染性疾病中升高的炎性细胞因子白细胞介素-1 β（IL-1 β）和肿瘤坏死因子-α（TNF）诱导HepG 2细胞中的低密度脂蛋白（LDL）受体转录，并且这种诱导可以解释与这些状态相关的低胆固醇血症。然而，姜黄素介导的LDL受体诱导的信号转导机制在很大程度上是未知的，在本研究中，我们检查了不同的丝裂原活化蛋白激酶（MAPK）途径的潜在参与。北方分析表明，IL-1 β或TNF显着增加LDL受体在HepG 2细胞的转录，而另一个严格调控的甾醇响应角鲨烯合酶基因的表达不受影响。IL-1 β胎面在加入细胞因子后15-30分钟，细胞因子的作用导致三个MAPK级联的瞬时激活，即p46/54（JNK）、p38（MAPK）和ERK-1/2，最大激活分别为20倍、25倍和3倍。PD 98059，一种特异性MAPK激酶活性抑制剂，抑制IL-1 β诱导的LDL受体表达。相反，SB 202190，一种特异性p38（MAPK）抑制剂，增强IL-1 β诱导的LDL受体表达，同时增加ERK-1/2活性。类似地，TNF诱导的LDL受体表达也需要ERK-1/2激活。最后，固醇抑制IL-1 β诱导的受体表达，而不影响ERK-1/2活化。这些结果表明，IL-IP或TNF诱导的LDL受体表达需要ERK-1/2激活，p38（MAPK）途径负调控LDL受体表达，甾醇抑制诱导在HepG 2细胞ERK-1/2下游的一个点。
The inflammatory cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF), elevated in inflammatory, malignant, and infectious diseases, induce low density lipoprotein (LDL) receptor transcription in HepG2 cells, and such are induction can account for hypocholesterolemia associated with these states. However, the signaling mechanisms of cytokine-mediated LDL receptor induction are largely unexplored, In the present studies, we examined the potential involvement of different mitogen-activated protein kinase (MAPK) pathways. Northern analysis demonstrated that IL-1 beta or TNF significantly increased LDL receptor transcript in HepG2 cells, whereas expression of another tightly regulated sterol-responsive squalene synthase gene was unaffected. IL-1 beta tread;ment resulted in transient activation of three MAPK cascades, namely p46/54(JNK), p38(MAPK), and ERK-1/2, with maximal activation of 20-, 25-, and 3-fold, respectively, occurring 15-30 min after cytokine addition. PD98059, a specific inhibitor of MAPK kinase activity, inhibited IL-lp-induced LDL receptor expression In contrast, SB202190, a specific inhibitor of p38(MAPK), enhanced IL-1 beta-induced LDL receptor expression, with a concomitant increase in ERK-1/2 activity. Similarly, TNF induced LDL receptor expression also required ERK-1/2 activation. Finally, sterols repressed IL-1 beta induced receptor expression, without affecting ERK-1/2 activation. These results show that IL-IP-or TNF-induced LDL receptor expression requires ERK-1/2 activation, that the p38(MAPK) pathway negatively regulates LDL receptor expression, and that sterols inhibit induction at a point downstream of ERK-1/2 in HepG2 cells.