G-CSF-mediated inhibition of JNK is a key mechanism for Lactobacillus rhamnosus-induced suppression of TNF production in macrophages
G-CSF-mediated inhibition of JNK is a key mechanism for Lactobacillus rhamnosus-induced suppression of TNF production in macrophages
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DOI：
10.1111/j.1462-5822.2006.00763.x
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发表时间：
2006-12-01
影响因子：
3.4
通讯作者：
Reid, Gregor
中科院分区：
文献类型：
--
作者：
Kim, Sung O.;Sheikh, Haroon I.;Reid, Gregor
鼠李糖乳杆菌是一种具有已知免疫调节特性的人类益生菌。迄今为止，这些免疫调节作用的机制还不清楚。为了阐明免疫调节信号机制，我们研究了两株L。鼠李属L. rhamnosus GG和GR-1在调节人单核细胞系THP-1和小鼠巨噬细胞中肿瘤坏死因子-α（TNF）的产生中的作用。利夫湖与致病性大肠杆菌GR- 12和粪肠球菌相比，rhamnosus GG和GR 1或其培养上清液诱导巨噬细胞产生少量TNF，但产生大量粒细胞集落刺激因子（G-CSF）。通过中和抗体和G-CSF受体敲除小鼠，我们证明了L. rhamnosus GG和GR-1处理的巨噬细胞抑制E.大肠杆菌或脂多糖激活的巨噬细胞通过旁分泌途径。G-CSF对TNF产生的抑制是通过激活STAT 3和随后抑制c-JunN-末端激酶（JNK）介导的。JNK激活的抑制需要STAT 3 α介导的从头蛋白质合成。这表明G-CSF在L.鼠李糖引发的抗炎作用及其抑制巨噬细胞产生TNF的机制。
Lactobacillus rhamnosus is a human commensal with known immunomodulatory properties. To date the mechanism of these immunomodulatory effects is not well understood. To unravel the immunomodulatory signalling mechanism, we investigated the effects of two strains of L. rhamnosus, L. rhamnosus GG and GR-1, in modulating production of tumour necrosis factor-alpha (TNF) in human monocytic cell line THP-1 and mouse macrophages. Live L. rhamnosus GG and GR1 or their spent culture supernatant induced minuscule amounts of TNF production but large quantities of granulocyte- colony stimulating factor (G-CSF) in macrophages compared with those induced by pathogenic Escherichia coli GR- 12 and Enterococcus faecalis. By using neutralizing antibodies and G-CSF receptor knockout mice, we demonstrated that G-CSF secreted from L. rhamnosus GG- and GR-1-exposed macrophages suppressed TNF production induced by E. coli- or lipopolysaccharide-activated macrophages through a paracrine route. The suppression of TNF production by G-CSF was mediated through activation of STAT3 and subsequent inhibition of c-JunN-terminal kinases (JNKs). The inhibition of JNK activation required STAT3 alpha-mediated de novo protein synthesis. This demonstrates a novel role of G-CSF in L. rhamnosus-triggered anti-inflammatory effects and its mechanism in the suppression of TNF production in macrophages.