Differential Expression of the Activator Protein 1 Transcription Factor Regulates Interleukin-1ß Induction of Interleukin 6 in the Developing Enterocyte.
Differential Expression of the Activator Protein 1 Transcription Factor Regulates Interleukin-1ß Induction of Interleukin 6 in the Developing Enterocyte.
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DOI：
10.1371/journal.pone.0145184
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Walker WA
中科院分区：
文献类型：
--
作者：
Cahill CM;Zhu W;Oziolor E;Yang YJ;Tam B;Rajanala S;Rogers JT;Walker WA
先天免疫反应的特征是转录因子、核因子 kappa B 和激活蛋白 1 及其下游靶标（包括白细胞介素 1β 和白细胞介素 6 在内的促炎细胞因子）的激活。这种反应在肠道中的正常发育对于人类新生儿的生存至关重要，延迟可能导致坏死性小肠结肠炎等毁灭性炎症性疾病的发生。先前的研究已经探讨了核因子 kappa B 在肠上皮细胞先天免疫反应发展中的作用，然而，尽管它在控制多种促炎细胞因子基因中发挥着核心作用，但激活蛋白 1 在肠上皮细胞这种反应中的作用却知之甚少。在这里，我们证明了经典激活蛋白 1 成员 cJun 和 cFos 及其上游激酶 JNK 和 p38 在未成熟肠上皮细胞中白细胞介素 6 的调节中发挥着重要作用。我们的数据支持这样一个模型，即 JNK 下游的 cFos/cJun 异二聚体和更有效的 cJun 同二聚体被效率较低的含有 JunD 的二聚体取代，导致成熟肠上皮细胞中观察到的对白细胞介素 1β 的反应性降低和白细胞介素 6 分泌减少。 JunB 在结肠细胞和结肠衍生组织中的组织特异性表达及其抑制 NCM-460 结肠细胞中白细胞介素 6 基因报告基因的白细胞介素 1β 诱导的能力表明，含有二聚体的 JunB 的诱导可能为在肠道该区域炎症发作期间控制 IL-6 分泌提供有吸引力的治疗策略
The innate immune response is characterized by activation of transcription factors, nuclear factor kappa B and activator protein-1 and their downstream targets, the pro-inflammatory cytokines including interleukin 1β and interleukin 6. Normal development of this response in the intestine is critical to survival of the human neonate and delays can cause the onset of devastating inflammatory diseases such as necrotizing enterocolitis. Previous studies have addressed the role of nuclear factor kappa B in the development of the innate immune response in the enterocyte, however despite its central role in the control of multiple pro-inflammatory cytokine genes, little is known on the role of Activator Protein 1 in this response in the enterocyte. Here we show that the canonical Activator Protein 1 members, cJun and cFos and their upstream kinases JNK and p38 play an essential role in the regulation of interleukin 6 in the immature enterocyte. Our data supports a model whereby the cFos/cJun heterodimer and the more potent cJun homodimer downstream of JNK are replaced by less efficient JunD containing dimers, contributing to the decreased responsiveness to interleukin 1β and decreased interleukin 6 secretion observed in the mature enterocyte. The tissue specific expression of JunB in colonocytes and colon derived tissues together with its ability to repress Interleukin-1β induction of an Interleukin-6 gene reporter in the NCM-460 colonocyte suggests that induction of JunB containing dimers may offer an attractive therapeutic strategy for the control of IL-6 secretion during inflammatory episodes in this area of the intestine