Yanagibashi Tsutomu, Nagai Yoshinori, Watanabe Yasuharu, Ikutani Masashi, Hirai Yoshikatsu, Takatsu Kiyoshi
Department of Immunobiology and Pharmacological Genetics, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama 930-0194, Japan; Toyama Prefectural Institute for Pharmaceutical Research, 17-1 Nakataikouyama, Imizu City, Toyama 939-0363, Japan.
Department of Immunobiology and Pharmacological Genetics, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, 2630 Sugitani, Toyama-shi, Toyama 930-0194, Japan; JST, PRESTO, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.
Immunol Lett. 2015 Jan;163(1):22-31. doi: 10.1016/j.imlet.2014.11.012. Epub 2014 Nov 22.
LPS stimulates the TLR4/Myeloid differentiation protein-2 (MD-2) complex and promotes a variety of immune responses in B cells. TLR4 has two main signaling pathways, MyD88 and Toll/IL-1R (TIR)-domain-containing adaptor-inducing interferon-β (TRIF) pathways, but relatively few studies have examined these pathways in B cells. In this study, we investigated MyD88- or TRIF-dependent LPS responses in B cells by utilizing their knockout mice. Compared with wild-type (WT) B cells, MyD88(-/-) B cells were markedly impaired in up-regulation of CD86 and proliferation induced by lipid A moiety of LPS. TRIF(-/-) B cells were also impaired in these responses compared with WT B cells, but showed better responses than MyD88(-/-) B cells. Regarding class switch recombination (CSR) elicited by lipid A plus IL-4, MyD88(-/-) B cells showed similar patterns of CSR to WT B cells. However, TRIF(-/-) B cells showed the impaired in the CSR. Compared with WT and MyD88(-/-) B cells, TRIF(-/-) B cells exhibited reduced cell division, fewer IgG1(+) cells per division, and decreased activation-induced cytidine deaminase (Aicda) mRNA expression in response to lipid A plus IL-4. Finally, IgG1 production to trinitrophenyl (TNP)-LPS immunization was impaired in TRIF(-/-) mice, while MyD88(-/-) mice exhibited increased IgG1 production. Thus, MyD88 and TRIF pathways differently regulate TLR4-induced immune responses in B cells.
脂多糖（LPS）刺激Toll样受体4（TLR4）/髓样分化蛋白2（MD - 2）复合物，并促进B细胞中的多种免疫反应。TLR4有两条主要的信号通路，即髓样分化因子88（MyD88）通路和含Toll/白细胞介素-1受体（TIR）结构域的接头蛋白诱导干扰素-β（TRIF）通路，但相对较少的研究在B细胞中检测这些通路。在本研究中，我们通过利用MyD88或TRIF基因敲除小鼠来研究B细胞中依赖MyD88或TRIF的LPS反应。与野生型（WT）B细胞相比，MyD88基因敲除（-/-）的B细胞在LPS脂多糖部分诱导的CD86上调和增殖方面明显受损。与WT B细胞相比，TRIF基因敲除（-/-）的B细胞在这些反应中也受损，但比MyD88基因敲除（-/-）的B细胞表现出更好的反应。关于脂多糖加白细胞介素-4引发的类别转换重排（CSR），MyD88基因敲除（-/-）的B细胞显示出与WT B细胞相似的CSR模式。然而，TRIF基因敲除（-/-）的B细胞在CSR方面受损。与WT和MyD88基因敲除（-/-）的B细胞相比，TRIF基因敲除（-/-）的B细胞在脂多糖加白细胞介素-4刺激下表现出细胞分裂减少、每次分裂产生的IgG1（+）细胞数量减少以及活化诱导的胞苷脱氨酶（Aicda）mRNA表达降低。最后，TRIF基因敲除（-/-）小鼠对三硝基苯（TNP）-LPS免疫的IgG1产生受损，而MyD88基因敲除（-/-）小鼠的IgG1产生增加。因此，MyD88和TRIF通路以不同方式调节B细胞中TLR4诱导的免疫反应。
