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Kaempferol 7-O-β-D-glucoside isolated from the leaves of Cudrania tricuspidata inhibits LPS-induced expression of pro-inflammatory mediators through inactivation of NF-κB, AP-1, and JAK-STAT in RAW 264.7 macrophages
Chemico-Biological Interactions ( IF 4.7 ) Pub Date : 2018-02-20 , DOI: 10.1016/j.cbi.2018.02.022
Seung-Bin Lee , Ji-Sun Shin , Hee-Soo Han , Hwi-Ho Lee , Jong Cheol Park , Kyung-Tae Lee

Kaempferol 7-O-β-D-glucoside (KPG), a natural flavonol isolated from Cudrania tricuspidata, has been reported to exert anti-cancer effects; however, its anti-inflammatory effects have not yet been reported. In this study, we demonstrate the suppressive effect of KPG on the production of nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages and mouse bone marrow-derived macrophages. KPG downregulated the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the protein level and iNOS, COX-2, TNF-α, IL-1β, and IL-6 at the mRNA level in LPS-treated RAW 264.7 macrophages. Moreover, we elucidated the underlying molecular mechanism, demonstrating that KPG attenuated LPS-induced nuclear factor-κB (NF-κB) activation by decreasing p65 nuclear translocation, inhibiting κBα (IκBα) phosphorylation/degradation and IκB kinaseα/β (IKKα/β) phosphorylation. KPG additionally reduced LPS-induced activator protein-1 (AP-1) activity by inhibiting c-Fos expression in the nucleus, though c-Jun was not affected. Furthermore, we revealed that KPG significantly abrogated the LPS-induced phosphorylation of signal transducer and activator of transcription (STAT) 1 (Ser 727, Tyr 701) and STAT3 (Tyr 705) through inhibiting the phosphorylation of Janus kinase (JAK) 1 and JAK2, its upstream activating proteins. Taken together, our data suggest that KPG induces anti-inflammatory activity by blocking NF-κB, AP-1, and JAK-STAT signaling pathways in LPS-treated RAW 264.7 macrophages, thus suppressing inflammatory mediators.



中文翻译:

Cu木叶片中分离得到的山酚7 - O - β -D-葡萄糖苷通过使RAW 264.7巨噬细胞中的NF-κB,AP-1和JAK-STAT失活来抑制LPS诱导的促炎性介质表达。

据报道,山茱emp酚7 - O - β -D-葡萄糖苷(KPG)是一种从Cu木(Cudrania tricuspidata)分离得到的天然黄酮醇,具有抗癌作用。但是,其抗炎作用尚未见报道。在这项研究中,我们证明了KPG对一氧化氮(NO),前列腺素E 2(PGE 2),脂多糖(LPS)诱导的RAW 264.7巨噬细胞和小鼠骨髓来源的巨噬细胞中的肿瘤坏死因子-α(TNF-α),白介素-1β(IL-1β)和白介素6(IL-6)。KPG在蛋白水平下调了诱导型一氧化氮合酶(iNOS)和环氧合酶2(COX-2)的表达,并在LPS的mRNA水平下调了iNOS,COX-2,TNF-α,IL-1β和IL-6的表达。处理的RAW 264.7巨噬细胞。此外,我们阐明了潜在的分子机制,证明KPG通过降低p65核易位,抑制κBα(IκBα)磷酸化/降解和IκB激酶α/β(IKKα/β)来减弱LPS诱导的核因子κB(NF-κB)活化。磷酸化。KPG还通过抑制细胞核中c-Fos的表达来降低LPS诱导的激活蛋白1(AP-1)活性,尽管c-Jun不受影响。此外,我们发现KPG通过抑制Janus激酶(JAK)1和JAK2的磷酸化显着消除了LPS诱导的信号转导和转录激活(STAT)1(Ser 727,Tyr 701)和STAT3(Tyr 705)的磷酸化。上游激活蛋白。两者合计,我们的数据表明KPG通过阻断LPS处理的RAW 264.7巨噬细胞中的NF-κB,AP-1和JAK-STAT信号传导途径来诱导抗炎活性,从而抑制炎症介质。

更新日期:2018-02-20
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