大黄酸在LPS活化巨噬细胞中发挥抗炎与促炎双向作用的机制研究
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摘要
由于甾体抗炎药和环氧酶抑制剂的使用可能引起严重的副作用,IκB激酶p(IKKβ)/核转录因子(NF-κB)这条炎症通路成为了最具前景的抗炎候选药物研究靶点。大黄酸是骨关节炎治疗药双醋瑞因的活性代谢产物(双醋瑞因在体内会完全代谢为大黄酸发挥作用),具有良好的抗炎特性且不会造成胃肠道损伤。然而,在对大黄酸的研究过程中,我们意外地发现大黄酸在LPS活化RAW264.7细胞中发挥既抗炎又促炎的双向作用：即大黄酸在抑制上清中一氧化氮(NO)和白细胞介素6(IL-6)生成的同时,还能促进肿瘤坏死因子α(TNF-α)、白细胞介素1β(IL-1β)和高迁移率族蛋白B1(HMGB1)的分泌。为了排除细胞特异性可能造成的结果误差,我们又采用了小鼠原代腹腔巨噬细胞重复实验,却得到了相同的结果。于是,我们进一步对其作用机制展开了研究。
结果发现,在转录水平,大黄酸能通过抑制IKKβ (IC50≈11.79μM)进而抑制NF-κB的活化及其下游调控的细胞因子诱生型一氧化氮合酶(iNOS)、TNF-α, IL-6和IL-1p的mRNA,呈现出单向的抗炎作用,提示大黄酸促进TNF-α和IL-1β的分泌是在转录后环节发挥作用的。由于HMGB1是高度保守的核蛋白,其转录也不受NF-κB的调控,故我们并未对其mRNA进行研究。为了排除抑制剂可能造成的脱靶效应,我们把IKKβ shRNA质粒转染至RAW264.7细胞中将胞内的IKKβ基因特异性“静默”掉,得到了稳定的IKKβ(-)细胞。结果显示,当IKKβ(-)细胞受到LPS刺激时,也表现出与大黄酸处理普通巨噬细胞之后类似的异常现象,表明IKKβ的抑制正是造成这种异常现象的主要原因。
由于IL-1β和HMGB1的分泌均需要依赖Caspase-1的活化,我们进一步研究了大黄酸对Caspase-1活性的影响。结果发现,虽然大黄酸对Caspase-1没有直接的作用,但可通过抑制胞内原位的IKKβ间接地增强Caspase-1活性,进而促进IL-1p和HMGB1的分泌,且这种促进作用可被大黄酸减少胞内超氧阴离子(O2.-)的作用所放大。此外,我们还发现,大黄酸对巨噬细胞的吞噬功能也有增强作用,且与对TNF-α释放的作用一样,该增强作用也不依赖LPS的存在,提示大黄酸可能通过另一未知的转录后机制促进TNF-α的分泌并增强巨噬细胞的吞噬功能。
本研究首次明确了大黄酸／双醋瑞因是一个IKKβ抑制剂,除了能帮助我们更为深入地了解这两个药物在炎症疾病中可能的作用机制之外,也为临床上更为合理地使用这两个药物提供了药理学依据。此外,本研究首次发现大黄酸作为一个天然的IKKβ小分子抑制剂在同一种细胞中展现出前所未知的既能抗炎又能促炎的双向作用,揭示了包括大黄酸和双醋瑞因在内的IKKP抑制剂在临床使用中的复杂性：在不同的组织器官和炎症进程中,由于微环境的不同,IKKβ本身具备的抗炎和促炎两种力量的主次程度不同,抑制IKKβ所产生的效果也可能完全不同。我们建议在投入使用IKKβ抑制剂之前,需要充分考察炎症所处的阶段以及炎症发生处的微环境,以保证所采取的治疗手段的科学性。
Since steroids and cyclooxygenase inhibitors may cause serious side effects, the IκB kinase (IKK)β/nuclear factor-KB (NF-κB) system becomes an intriguing candidate anti-inflammatory target. Rhein, the active metabolite of diacerein, possesses anti-inflammatory ability with gastrointestinal protective effect. However, in our preliminary study, we accidentally found that rhein showed both anti-and pro-inflammatory activities in lipopolysaccharide (LPS)-activated macrophages:rhein reduces proinflammatory mediators nitric oxide (NO) and interleukin-6(IL-6), but enhances tumor necrosis factor-a (TNF-a), interleukin-1β (IL-1β) and high mobility group box1(HMGB1) release. To exclude the effect of cell specificity, we carried out parallel experiments in Balb/c mice peritoneal macrophages. Similar results were also observed in mice peritoneal macrophages. Thus, in this study, we explored the underlying molecular mechanisms of the dual effect of rhein.
In LPS-activated macrophages, the supernatant NO was determined by Griess method, other proinflammatory mediators IL-6, TNF-a, IL-1β and HMGB1were assayed by ELISA kits. The transcriptional levels of proinflammatory cytokines were determined by Western blot and qPCR, respectively. All protein expressions were determined by Western blot. NF-κB and AP-1activation were investigated by luciferase assay. IKKP kinase activity assay was performed using IκBa as a substrate. IKKβ (-) cells were obtained by using IKKP shRNA plasmid.
The obtained results indicated that rhein inhibits LPS-induced NF-κB activation and sequentially suppresses its downstream inducible nitric oxide synthase (iNOS), IL-6, TNF-a and IL-1β transcriptions and supernatant NO and IL-6levels by inhibiting IKKP (IC50≈11.79μM). To verify whether the pro-and anti-inflammatory actions of rhein attribute to the IKKP inhibition and exclude the off-target effects by IKKβ inhibitors, we conditionally knocked down the IKKβ gene in RAW264.7cells using KKβ shRNA plasmid and obtained stable IKKP (-) cells. Its responses to LPS were similar to rhein-treated macrophages, suggesting that rhein exerted anti-and pro-inflammatory activities by virtue of targeting IKKβ inhibition, In the meantime, rhein enhances the activity of caspase-1through inhibiting intracellular (in situ) IKβ, in turn increasing the IL-1β and HMGB1release, which can be amplified by rhein's reductive effect on intracellular superoxide anion (O2-). Unexpectedly, it is because of IKKβ inhibition that rhein significantly enhances TNF-a secretion and phagocytosis in macrophages with or without LPS.
In summary, the above results indicate that rhein exerts anti-and pro-inflammatory activities by targeting IKKβ inhibition, providing a molecular mechanism for the unanticipated role of rhein in macrophages for the first time. Furthermore, our study also highlights the potential complications of IKKβ inhibitors (e.g. rhein and diacerein, etc.) application in inflammation disorders, for the overall effects of IKKβ inhibition in different organ systems and disease processes are not easily predictable under all circumstances. Considering diacerein having been widely used clinically and its apparent safety in patients, we conclude that direct inhibition IKKβ is a hitherto unrecognized property of rhein or diacerein, which may lead to the development of previously undescribed therapeutic repositioning strategies for the treatment of various human inflammatory diseases, as well as OA. Although IKKβ inhibitors are likely to be potent anti-inflammatory agents, the fact that IKKβ displays opposite functions in macrophages raises the question whether IKKP inhibitors are excellent anti-inflammatory agents in various tissues or different stages of inflammatory diseases. Answering the question would be good for the rational use of rhein or diacerein clinically.
结果发现,在转录水平,大黄酸能通过抑制IKKβ (IC50≈11.79μM)进而抑制NF-κB的活化及其下游调控的细胞因子诱生型一氧化氮合酶(iNOS)、TNF-α, IL-6和IL-1p的mRNA,呈现出单向的抗炎作用,提示大黄酸促进TNF-α和IL-1β的分泌是在转录后环节发挥作用的。由于HMGB1是高度保守的核蛋白,其转录也不受NF-κB的调控,故我们并未对其mRNA进行研究。为了排除抑制剂可能造成的脱靶效应,我们把IKKβ shRNA质粒转染至RAW264.7细胞中将胞内的IKKβ基因特异性“静默”掉,得到了稳定的IKKβ(-)细胞。结果显示,当IKKβ(-)细胞受到LPS刺激时,也表现出与大黄酸处理普通巨噬细胞之后类似的异常现象,表明IKKβ的抑制正是造成这种异常现象的主要原因。
由于IL-1β和HMGB1的分泌均需要依赖Caspase-1的活化,我们进一步研究了大黄酸对Caspase-1活性的影响。结果发现,虽然大黄酸对Caspase-1没有直接的作用,但可通过抑制胞内原位的IKKβ间接地增强Caspase-1活性,进而促进IL-1p和HMGB1的分泌,且这种促进作用可被大黄酸减少胞内超氧阴离子(O2.-)的作用所放大。此外,我们还发现,大黄酸对巨噬细胞的吞噬功能也有增强作用,且与对TNF-α释放的作用一样,该增强作用也不依赖LPS的存在,提示大黄酸可能通过另一未知的转录后机制促进TNF-α的分泌并增强巨噬细胞的吞噬功能。
本研究首次明确了大黄酸／双醋瑞因是一个IKKβ抑制剂,除了能帮助我们更为深入地了解这两个药物在炎症疾病中可能的作用机制之外,也为临床上更为合理地使用这两个药物提供了药理学依据。此外,本研究首次发现大黄酸作为一个天然的IKKβ小分子抑制剂在同一种细胞中展现出前所未知的既能抗炎又能促炎的双向作用,揭示了包括大黄酸和双醋瑞因在内的IKKP抑制剂在临床使用中的复杂性：在不同的组织器官和炎症进程中,由于微环境的不同,IKKβ本身具备的抗炎和促炎两种力量的主次程度不同,抑制IKKβ所产生的效果也可能完全不同。我们建议在投入使用IKKβ抑制剂之前,需要充分考察炎症所处的阶段以及炎症发生处的微环境,以保证所采取的治疗手段的科学性。
Since steroids and cyclooxygenase inhibitors may cause serious side effects, the IκB kinase (IKK)β/nuclear factor-KB (NF-κB) system becomes an intriguing candidate anti-inflammatory target. Rhein, the active metabolite of diacerein, possesses anti-inflammatory ability with gastrointestinal protective effect. However, in our preliminary study, we accidentally found that rhein showed both anti-and pro-inflammatory activities in lipopolysaccharide (LPS)-activated macrophages:rhein reduces proinflammatory mediators nitric oxide (NO) and interleukin-6(IL-6), but enhances tumor necrosis factor-a (TNF-a), interleukin-1β (IL-1β) and high mobility group box1(HMGB1) release. To exclude the effect of cell specificity, we carried out parallel experiments in Balb/c mice peritoneal macrophages. Similar results were also observed in mice peritoneal macrophages. Thus, in this study, we explored the underlying molecular mechanisms of the dual effect of rhein.
In LPS-activated macrophages, the supernatant NO was determined by Griess method, other proinflammatory mediators IL-6, TNF-a, IL-1β and HMGB1were assayed by ELISA kits. The transcriptional levels of proinflammatory cytokines were determined by Western blot and qPCR, respectively. All protein expressions were determined by Western blot. NF-κB and AP-1activation were investigated by luciferase assay. IKKP kinase activity assay was performed using IκBa as a substrate. IKKβ (-) cells were obtained by using IKKP shRNA plasmid.
The obtained results indicated that rhein inhibits LPS-induced NF-κB activation and sequentially suppresses its downstream inducible nitric oxide synthase (iNOS), IL-6, TNF-a and IL-1β transcriptions and supernatant NO and IL-6levels by inhibiting IKKP (IC50≈11.79μM). To verify whether the pro-and anti-inflammatory actions of rhein attribute to the IKKP inhibition and exclude the off-target effects by IKKβ inhibitors, we conditionally knocked down the IKKβ gene in RAW264.7cells using KKβ shRNA plasmid and obtained stable IKKP (-) cells. Its responses to LPS were similar to rhein-treated macrophages, suggesting that rhein exerted anti-and pro-inflammatory activities by virtue of targeting IKKβ inhibition, In the meantime, rhein enhances the activity of caspase-1through inhibiting intracellular (in situ) IKβ, in turn increasing the IL-1β and HMGB1release, which can be amplified by rhein's reductive effect on intracellular superoxide anion (O2-). Unexpectedly, it is because of IKKβ inhibition that rhein significantly enhances TNF-a secretion and phagocytosis in macrophages with or without LPS.
In summary, the above results indicate that rhein exerts anti-and pro-inflammatory activities by targeting IKKβ inhibition, providing a molecular mechanism for the unanticipated role of rhein in macrophages for the first time. Furthermore, our study also highlights the potential complications of IKKβ inhibitors (e.g. rhein and diacerein, etc.) application in inflammation disorders, for the overall effects of IKKβ inhibition in different organ systems and disease processes are not easily predictable under all circumstances. Considering diacerein having been widely used clinically and its apparent safety in patients, we conclude that direct inhibition IKKβ is a hitherto unrecognized property of rhein or diacerein, which may lead to the development of previously undescribed therapeutic repositioning strategies for the treatment of various human inflammatory diseases, as well as OA. Although IKKβ inhibitors are likely to be potent anti-inflammatory agents, the fact that IKKβ displays opposite functions in macrophages raises the question whether IKKP inhibitors are excellent anti-inflammatory agents in various tissues or different stages of inflammatory diseases. Answering the question would be good for the rational use of rhein or diacerein clinically.
引文
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[1]Fontaine C, Rigamonti E, Nohara A, Gervois P, Teissier E, Fruchart JC, Staels B and Chinetti-Gbaguidi G. Liver X receptor activation potentiates the lipopolysaccharide response in human macrophages [J]. Circ. Res.,2007,101(1): 40-49.
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[3]Nam NH. Naturally occurring NF-kappaB inhibitors [A]. Mini. Rev. Med. Chem., 2006,6(8):945-951.
[4]Wang GJ, Chen SM, Chen WC, Chang YM and Lee TH. Selective inducible nitric oxide synthase suppression by new bracteanolides from Murdannia bracteata [J]. J Ethnopharmacol.,2007,112(2):221-227.
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[8]Stuart LM and Ezekowitz RA. Phagocytosis:elegant complexity [A]. Immunity, 2005,22(5):539-550.
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