Role of the suppressor of cytokine signaling-3 in mediating the inhibitory effects of interleukin-1β on the growth hormone-dependent transcription of the acid-labile subunit gene in liver cells
Role of the suppressor of cytokine signaling-3 in mediating the inhibitory effects of interleukin-1β on the growth hormone-dependent transcription of the acid-labile subunit gene in liver cells
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DOI：
10.1074/jbc.275.6.3841
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发表时间：
2000-02-11
影响因子：
4.8
通讯作者：
Ooi, GT
中科院分区：
文献类型：
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作者：
Boisclair, YR;Wang, JR;Ooi, GT
在败血症、炎症和感染等分解代谢疾病期间，肝脏会出现生长激素（GH）抵抗状态。这部分归因于促炎细胞因子白细胞介素-1 β（IL-1 β）的产生增加。为了确定IL-1 β如何诱导GH抗性，我们研究了酸不稳定亚基（ALS）基因，其肝脏转录通过Janus激酶信号转导和转录激活因子（JAK-STAT）途径被GH增加。IL-1 β降低GH刺激大鼠原代肝细胞中ALS mRNA的能力和H4-II-E大鼠肝癌细胞中ALS启动子的活性。这种抑制作用依赖于ALSGAS 1，ALSGAS 1是一种类似于γ-干扰素激活序列的元件，可介导GH的转录作用。IL-1 β的抑制作用也与慢性（8和24小时）后STATE与该元素的GH依赖性结合减少有关，但与急性治疗（15分钟）后无关。由于这些结果表明IL-1 β的抑制是间接的，因此在肝细胞中检测了最近发现的细胞因子作用抑制因子（SOCS）的表达。IL-1 β没有改变SOCS 1、SOCS 2和CIS的表达，表明它们不参与。相比之下，IL-1 β在处理24小时后使SOCS 3 mRNA增加8倍，而GH没有影响。SOCS 3的强制表达在降低H4-II-E大鼠肝癌细胞中GH对ALS启动子活性的诱导方面与IL-1 β一样有效。在原代大鼠肝细胞中观察到类似结果。我们的结论是，由IL-1 β诱导SOCS 3有助于在肝脏中GH抗性的发展，并代表了一种机制，通过这种机制，细胞因子如IL-1 β与细胞因子使用JAK-STAT途径相互作用。
During catabolic diseases such as sepsis, inflammation, and infection, a state of growth hormone (GH) resistance develops in liver. This has been attributed in part to increased production of the proinflammatory cytokine interleukin-1 beta (IL-1 beta). To determine how IL-1 beta induces GH resistance, we studied the acid-labile subunit (ALS) gene whose hepatic transcription is increased by GH via the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. IL-1 beta reduced the ability of GH to stimulate ALS mRNA in rat primary hepatocytes and ALS promoter activity in H4-II-E rat hepatoma cells. This inhibition was dependent on ALSGAS1, an element resembling a gamma-interferon activated sequence that mediates the transcriptional effects of GH. Inhibition by IL-1 beta was also associated with a reduction of GH-dependent binding of STATE to this element after chronic (8 and 24 h), but not after acute treatment (15 min). Because these results indicated that the inhibition by IL-1 beta was indirect, expression of the recently discovered suppressors of cytokine action (SOCS) was examined in liver cells. IL-1 beta did not alter the expression of SOCS1, SOCS2, and CIS, indicating that they are not involved. In contrast, IL-1 beta increased SOCS3 mRNA by 8-fold after 24 h of treatment, whereas GH had no effect. Forced expression of SOCS3 was just as effective as IL-1 beta in reducing the GH induction of ALS promoter activity in H4-II-E rat hepatoma cells. Similar results were observed in primary rat hepatocytes. We conclude that the induction of SOCS3 by IL-1 beta contributes to the development of GH resistance in liver, and represents a mechanism by which cytokines such as IL-1 beta cross-talk with cytokines using the JAK-STAT pathway.