Inhibitory Effects of the Lactobacillus rhamnosus GG Effector Protein HM0539 on Inflammatory Response Through the TLR4/MyD88/NF-кB Axis.
Inhibitory Effects of the Lactobacillus rhamnosus GG Effector Protein HM0539 on Inflammatory Response Through the TLR4/MyD88/NF-кB Axis.
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鼠李糖乳杆菌GG效应蛋白HM0539通过TLR4/MyD88/NF-kB轴对炎症反应的抑制作用
DOI：
10.3389/fimmu.2020.551449
复制
发表时间：
2020
影响因子：
7.3
通讯作者：
Cao H
中科院分区：
文献类型：
--
作者：
Li Y;Yang S;Lun J;Gao J;Gao X;Gong Z;Wan Y;He X;Cao H
炎症性肠病（IBD）是一种慢性和复发性肠道炎性疾病，目前尚无有效的治疗方法。益生菌因其在肠道健康问题上的突出优势而受到广泛关注。在以前的研究中，一种新的可溶性蛋白，HM 0539，这是来自鼠李糖乳杆菌GG（LGG），显示出显着的保护作用，对小鼠结肠炎，但没有提供明确的确切机制，这种效果。在本研究中，我们假设HM 0539的保护功能可能来自其对TLR 4/Myd 88/NF-κB轴信号通路的调节，这是广泛参与炎症反应调节的关键通路。为了检验这一假设，在脂多糖（LPS）刺激的RAW 264.7巨噬细胞和葡聚糖硫酸钠（DSS）诱导的小鼠结肠炎中测定了HM 0539的潜在抗炎作用和相关机制。我们的研究结果表明，HM 0539通过下调环氧合酶-2（考克斯-2）和诱导型一氧化氮合酶（iNOS）各自启动子的激活来抑制其表达，从而抑制前列腺素E2（PGE 2）和一氧化氮（NO）的产生。同时，我们证明HM 0539可以通过降低TLR 4的活化和抑制MyD 88的转导来最终调节远端NF-κB的活化。然而，尽管TLR 4或MyD 88的过表达明显逆转了HM 0539对LPS诱导的炎症的作用，但HM 0539仍然保留了一定的抗炎活性。与体外研究结果一致，我们发现HM 0539在很大程度上抑制了与结肠组织中TLR 4/Myd 88/NF-κB轴激活抑制相关的炎症介质的产生。总之，HM 0539被证明是一种有前景的抗炎药物，至少部分通过下调TLR 4-MyD 88轴以及下游MyD 88依赖性活化NF-κB信号传导，因此可能被视为IBD的潜在治疗选择。
Inflammatory bowel disease (IBD) is a chronic and relapsing intestinal inflammatory condition with no effective treatment. Probiotics have gained wide attention because of their outstanding advantages in intestinal health issues. In previous studies, a novel soluble protein, HM0539, which is derived from Lactobacillus rhamnosus GG (LGG), showed significant protective effects against murine colitis, but no clear precise mechanism for this effect was provided. In this study, we hypothesized that the protective function of HM0539 might be derived from its modulation of the TLR4/Myd88/NF-κB axis signaling pathway, which is a critical pathway widely involved in the modulation of inflammatory responses. To test this hypothesis, the underlying anti-inflammatory effects and associated mechanisms of HM0539 were determined both in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and in dextran sulfate sodium (DSS)-induced murine colitis. Our results showed that HM0539 inhibited the expression of cyclooxygenase-2 (COX-2) and the expression inducible nitric oxide synthase (iNOS) by down-regulating the activation of their respective promoter, and as a result this inhibited the production of prostaglandin E2 (PGE2) and nitric oxide (NO). Meanwhile, we demonstrated that HM0539 could ultimately modulate the activation of distal NF-κB by reducing the activation of TLR4 and suppressing the transduction of MyD88. However, even though the overexpression of TLR4 or MyD88 obviously reversed the effect of HM0539 on LPS-induced inflammation, HM0539 still retained some anti-inflammatory activity. Consistent with the in vitro findings, we found that HM0539 inhibited to a great extent the production of inflammatory mediators associated with the suppression of the TLR4/Myd88/NF-κB axis activation in colon tissue. In conclusion, HM0539 was shown to be a promising anti-inflammatory agent, at least in part through its down-regulation of the TLR4-MyD88 axis as well as of the downstream MyD88-dependent activated NF-κB signaling, and hence might be considered as a potential therapeutic option for IBD.
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DOI：
10.1007/s00424-017-1958-2
发表时间：
2017-04
期刊：
Pflugers Archiv : European journal of physiology
影响因子：
--
作者：
Grainger JR;Konkel JE;Zangerle-Murray T;Shaw TN
通讯作者：
Shaw TN
影响因子：
29
作者：
Baker RG;Hayden MS;Ghosh S
通讯作者：
Ghosh S
影响因子：
8.7
作者：
Bain CC;Mowat AM
通讯作者：
Mowat AM
影响因子：
4.4
作者：
Bagchi, Aranya;Herrup, Elizabeth A.;Hellman, Judith
通讯作者：
Hellman, Judith
影响因子：
5.9
作者：
Deshpande G;Athalye-Jape G;Patole S
通讯作者：
Patole S