Resveratrol inhibits high glucose-induced PI3K/Akt/ERK-dependent interleukin-17 expression in primary mouse cardiac fibroblasts
Resveratrol inhibits high glucose-induced PI3K/Akt/ERK-dependent interleukin-17 expression in primary mouse cardiac fibroblasts
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DOI：
10.1152/ajpheart.01363.2007
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发表时间：
2008-05-01
影响因子：
4.8
通讯作者：
Chandrasekar, Bysani
中科院分区：
文献类型：
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作者：
Venkatachalam, Kaliyamurthi;Mummidi, Srinivas;Chandrasekar, Bysani
我们研究了促炎细胞因子白细胞介素(IL)-17在心脏成纤维细胞中的表达及其在高糖（HG）作用下的诱导作用。我们的研究结果表明，原代小鼠心脏成纤维细胞（mcf）分泌低基础水平的IL-17， HG （25 mM d -葡萄糖）与低糖（5 mM d -葡萄糖+ 20 mM甘露醇）相比，显著增强了IL-17的分泌。HG通过转录和转录后机制诱导IL-17 mRNA表达。HG诱导磷酸肌肽3-激酶[PI3K]；被腺病毒（Ad）抑制。显性阴性（dn） PI3Kp85], Akt（受Ad抑制）。dnAkt1)和ERK（被PD-98059抑制）激活，并通过PI3K -> 3Akt -> ERK依赖性信号诱导IL-17表达。此外，mcf同时表达IL-17受体A和C，尽管IL-17RA上调，但HG无法调节IL-17RC的表达。此外，IL-17刺激mcf产生净胶原蛋白。植物抗毒素白藜芦醇预处理可阻断hg诱导的PI3K-、Akt-和erk依赖性IL-17的表达。这些结果表明：1)心肌成纤维细胞表达IL-17及其受体；2) HG上调IL-17和IL-17RA，提示IL-17信号通路在高血糖中存在正扩增环；3) IL-17促进净胶原生成；4)白藜芦醇可以抑制hg诱导的这些变化。因此，在高血糖状态下，IL-17可能通过自分泌和旁分泌机制增强心肌炎症、损伤和重构，而白藜芦醇在改善这一作用方面具有治疗潜力。
We investigated the expression of the proinflammatory cytokine interleukin (IL)-17 in cardiac fibroblasts and its induction by high glucose (HG). Our results show that primary mouse cardiac fibroblasts (mCFs) secrete low basal levels of IL-17 and that HG (25 mM D-glucose) as opposed to low glucose (5 mM D-glucose + 20 mM mannitol) significantly enhances its secretion. HG induces IL-17 mRNA expression by both transcriptional and posttranscriptional mechanisms. HG induces phosphoinositide 3-kinase [PI3K; inhibited by adenoviral (Ad). dominant negative (dn) PI3Kp85], Akt (inhibited by Ad.dnAkt1), and ERK (inhibited by PD-98059) activation and induces IL-17 expression via PI3K -> 3Akt -> ERK-dependent signaling. Moreover, mCFs express both IL-17 receptors A and C, and although IL-17RA is upregulated, HG fails to modulate IL-17RC expression. Furthermore, IL-17 stimulates net collagen production by mCFs. Pretreatment with the phytoalexin resveratrol blocks HG-induced PI3K-, Akt-, and ERK-dependent IL-17 expression. These results demonstrate that 1) cardiac fibroblasts express IL-17 and its receptors; 2) HG upregulates IL-17 and IL-17RA, suggesting a positive amplification loop in IL-17 signaling in hyperglycemia; 3) IL-17 enhances net collagen production; and 4) resveratrol can inhibit these HG-induced changes. Thus, in hyperglycemic conditions, IL-17 may potentiate myocardial inflammation, injury, and remodeling through autocrine and paracrine mechanisms, and resveratrol has therapeutic potential in ameliorating this effect.