Kotaki Ryutaro, Wajima Shun-ichi, Shiokawa Aya, Hachimura Satoshi
Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, Japan.
Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, Japan.
Immunobiology. 2015 Jun;220(6):734-43. doi: 10.1016/j.imbio.2014.12.022. Epub 2015 Jan 8.
In the intestine, immune responses to commensal microbes should be regulated precisely. This regulation is achieved partly by dendritic cells (DCs), which recognize microbes through Toll-like receptors (TLRs). Although TLR responses have been intensely studied, cross-talk between individual TLRs remains unclear. The present study shows that TLR2 suppressed TLR9-induced Il12b gene expression and subsequent interleukin (IL)-12 and IL-23 production in DCs from Peyer's patch, a lymphoid tissue in the small intestine. The DCs expressed Il12b gene and produced IL-12 and IL-23 in response to TLR9 stimulation, and these responses were suppressed when the DCs were stimulated simultaneously with TLR2. The suppression was also observed in the non-intestinal DCs, such as spleen DCs and bone marrow-derived DCs. Peyer's patch DCs expressed Il12b gene also in response to TLR7 or CD40 stimulation, but these responses were not suppressed by simultaneous TLR2 stimulation. In addition, TLR9-induced Tnf and Il6 gene expression was not suppressed by TLR2. Furthermore, the supernatant of TLR2-stimulated DCs could not suppress TLR9-induced Il12b gene expression. These results suggest that TLR2 suppress TLR9-induced responses selectively, and this suppression is not mediated by secretory factors. The suppressive TLR cross-talk might play a certain role in preventing excess inflammatory responses to commensal microbes in the intestine and may have implications for the therapeutic strategies for intestinal inflammatory diseases, autoimmune diseases and cancer.
在肠道中，对共生微生物的免疫反应应得到精确调节。这种调节部分是由树突状细胞（DCs）实现的，树突状细胞通过Toll样受体（TLRs）识别微生物。尽管对TLR反应进行了深入研究，但各个TLR之间的相互作用仍不清楚。本研究表明，TLR2抑制了来自派尔集合淋巴结（小肠中的一种淋巴组织）的DCs中TLR9诱导的Il12b基因表达以及随后的白细胞介素（IL）-12和IL-23的产生。DCs在受到TLR9刺激时表达Il12b基因并产生IL-12和IL-23，而当DCs同时受到TLR2刺激时，这些反应受到抑制。在非肠道DCs中，如脾脏DCs和骨髓来源的DCs中也观察到了这种抑制作用。派尔集合淋巴结DCs在受到TLR7或CD40刺激时也表达Il12b基因，但这些反应不会被同时的TLR2刺激所抑制。此外，TLR9诱导的Tnf和Il6基因表达不会被TLR2抑制。此外，TLR2刺激的DCs的上清液不能抑制TLR9诱导的Il12b基因表达。这些结果表明，TLR2选择性地抑制TLR9诱导的反应，并且这种抑制不是由分泌因子介导的。抑制性的TLR相互作用可能在预防肠道中对共生微生物的过度炎症反应中发挥一定作用，并且可能对肠道炎症性疾病、自身免疫性疾病和癌症的治疗策略具有启示意义。
