Molecular events in the activation of B cells and macrophages by a non-microbial TLR4 agonist, G1-4A from Tinospora cordifolia
Molecular events in the activation of B cells and macrophages by a non-microbial TLR4 agonist, G1-4A from Tinospora cordifolia
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DOI：
10.1016/j.imlet.2009.02.005
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发表时间：
2009-03-24
影响因子：
4.4
通讯作者：
Sainis, Krishna Balaji
中科院分区：
文献类型：
--
作者：
Raghu, Rashmi;Sharma, Deepak;Sainis, Krishna Balaji
G1-4A是一种来自印度药用植物青牛胆的多糖，最近被证明可以通过调节促炎细胞因子来保护小鼠免受感染性休克。G1-4A还多克隆地激活B细胞。本报告详细描述了与G1- 4A诱导的免疫调节在体外和体内的分子事件。G1-4A处理导致淋巴细胞中CD 69表达增加。G1- 4A诱导的B细胞增殖被PI 3 K抑制剂Ly 294002、mTOR抑制剂雷帕霉素和NF-κ B抑制剂白花丹素完全抑制。G1- 4 A激活Akt、ERK和JNK，最终导致IKK的激活、I κ B-α的降解和NF-κ B的核转位。给予小鼠G1-4A导致脾肿大和T细胞、B细胞和巨噬细胞数量增加。这种脾细胞构成的增加是由于淋巴细胞的体内增殖和抗凋亡基因的上调。抗TLR-4-MD 2复合物抗体抑制G1- 4A诱导的B细胞增殖和I κ B-α降解，表明TLR-4是B细胞上G1-4A的受体。发现G1-4A对RAW 264.7巨噬细胞的激活依赖于ERK和NF-κ B介导的信号。从G1-4A处理的小鼠中分离的腹膜渗出细胞（PEC）的吞噬指数显著高于来自对照小鼠的PEC。G1-4A给药也增加了PEC中CD 11b（+）细胞的数量，而PEC总数没有增加。因此，目前对G1-4A（一种新型非微生物TLR 4激动剂）作用的分子机制的理解将为其作为免疫调节剂和佐剂的应用铺平道路。(C)2009 Elsevier B. V.保留所有权利。
G1-4A, a polysaccharide from an Indian medicinal plant Tinospora cordifolia, was recently shown to protect mice against septic shock by modulating the proinflammatory cytokines. G1-4A also activated B cells polyclonally. The present report describes in detail the molecular events associated with G1-4A-induced immunomodulation in vitro and in vivo. G1-4A treatment led to an increase in the CD69 expression in lymphocytes. G1-4A-induced proliferation of B cells was completely inhibited by PI3K inhibitor Ly294002, mTOR inhibitor rapamycin and NF-kappa B inhibitor plumbagin. Akt, ERK and JNK were activated by G1-4A which finally resulted in the activation of IKK, degradation of I kappa B-alpha and translocation of NF-kappa B to the nucleus. Administration of G1-4A to mice led to splenomegaly and an increase in the numbers of T cells, B cells and macrophages. This increase in spleen cellularity was due to in vivo proliferation of lymphocytes and upregulation of anti-apoptotic genes. Anti-TLR4-MD2 complex antibody inhibited G1-4A-induced B cell proliferation and degradation of I kappa B-alpha suggesting that TLR-4 was a receptor for G1-4A on B cells. Activation of RAW 264.7 macrophages by G1-4A was found to be dependent on ERK and NF-kappa B-mediated signals. The phagocytosis index in peritoneal exudate cells (PEC) isolated from G1-4A treated mice was significantly higher as compared to that in PEC from control mice. G1-4A administration also increased the number of CD11b(+) cells in the PEC without an increase in the total number of PEC. Thus the present understanding of the molecular mechanism of action of G1-4A, a novel non-microbial TLR4 agonist, will pave the way for its application as an immunomodulator and adjuvant. (C) 2009 Elsevier B.V. All rights reserved.