IL-1β and TNFα Cooperativity in Regulating IL-6 Expression in Adipocytes Depends on CREB Binding and H3K14 Acetylation.
IL-1β and TNFα Cooperativity in Regulating IL-6 Expression in Adipocytes Depends on CREB Binding and H3K14 Acetylation.
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DOI：
10.3390/cells10113228
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发表时间：
2021-11-19
期刊：
影响因子：
6
通讯作者：
Ahmad R
中科院分区：
文献类型：
--
作者：
Al-Roub A;Al Madhoun A;Akhter N;Thomas R;Miranda L;Jacob T;Al-Ozairi E;Al-Mulla F;Sindhu S;Ahmad R
IL-6被发现在肥胖个体的脂肪组织中过度表达，这可能导致胰岛素抵抗。然而，肥胖环境下脂肪细胞中 IL-6 的调节仍有待探索。由于肥胖脂肪组织中 IL-1β 和 TNFα 增加并促进炎症，我们研究了 IL-1β 和 TNFα 之间的合作是否影响 IL-6 的产生。我们的数据表明，IL-1β 和 TNFα 协同增强 3T3L-1 脂肪细胞中 IL-6 的表达。在从皮下和内脏脂肪中分离的人类脂肪细胞中也观察到类似的结果。尽管从瘦脂肪组织和肥胖脂肪组织中分离的脂肪细胞在与 IL-1β/TNFα 一起孵育时对产生 IL-6 表现出相似的反应，但来自肥胖组织的脂肪细胞中 IL-6 的分泌更高。 TNFα 处理增强了 CRE 位点处的 CREB 结合，IL-1β 进一步增强了这种结合，并且与 CRE 位点处的组蛋白乙酰化升高相关。另一方面，IL-1β 治疗介导 C/EBPβ 与 NF-IL-6 一致性结合，但不足以介导显着的组蛋白乙酰化。有趣的是，两种刺激因子的治疗都会增强 CREB 结合和 H3K14 乙酰化。此外，漆树酸或姜黄素抑制组蛋白乙酰化可减少 IL-6 的产生。值得注意的是，曲古抑菌素 A (TSA) 对组蛋白脱乙酰酶 (HDAC) 活性的抑制导致 IL-1β 和 TNFα 联合治疗脂肪细胞时 IL-6 表达进一步升高。总之，我们的结果表明，IL-1β 和 TNFα 之间存在依赖于 CREB 结合和 H3K14 乙酰化的附加相互作用，并导致脂肪细胞中 IL-6 表达升高，从而在肥胖等环境中提供了 IL-1β、TNFα 和 IL-6 之间有趣的病理生理学联系。
IL-6 was found to be overexpressed in the adipose tissue of obese individuals, which may cause insulin resistance. However, the regulation of IL-6 in adipocytes in obesity setting remains to be explored. Since IL-1β and TNFα are increased in obese adipose tissue and promote inflammation, we investigated whether cooperation between IL-1β and TNFα influences the production of IL-6. Our data show that IL-1β and TNFα cooperatively enhance IL-6 expression in 3T3L-1 adipocytes. Similar results were seen in human adipocytes isolated from subcutaneous and visceral fat. Although adipocytes isolated from lean and obese adipose tissues showed similar responses for production of IL-6 when incubated with IL-1β/TNFα, secretion of IL-6 was higher in adipocytes from obese tissue. TNFα treatment enhanced CREB binding at CRE locus, which was further enhanced with IL-1β, and was associated with elevated histone acetylation at CRE locus. On the other hand, IL-1β treatments mediated C/EBPβ binding to NF-IL-6 consensus, but not sufficiently to mediate significant histone acetylation. Interestingly, treatment with both stimulatory factors amplifies CREB binding and H3K14 acetylation. Furthermore, histone acetylation inhibition by anacardic acid or curcumin reduces IL-6 production. Notably, inhibition of histone deacetylase (HDAC) activity by trichostatin A (TSA) resulted in the further elevation of IL-6 expression in response to combined treatment of adipocytes with IL-1β and TNFα. In conclusion, our results show that there is an additive interaction between IL-1β and TNFα that depends on CREB binding and H3K14 acetylation, and leads to the elevation of IL-6 expression in adipocytes, providing interesting pathophysiological connection among IL-1β, TNFα, and IL-6 in settings such as obesity.
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