Yamashita Maya, Ukibe Ken, Matsubara Yumi, Hosoya Tomohiro, Sakai Fumihiko, Kon Shigeyuki, Arima Yasunobu, Murakami Masaaki, Nakagawa Hisako, Miyazaki Tadaaki
Milk Science Research Institute, Megmilk Snow Brand Co., Ltd., Saitama, Japan.
Department of Probiotics Immunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
Front Microbiol. 2018 Jan 22;8:2596. doi: 10.3389/fmicb.2017.02596. eCollection 2017.
We recently reported that SBT2171 (LH2171) inhibited the proliferation and inflammatory cytokine production of primary immune cells , and alleviated collagen-induced arthritis (CIA) in mice, a model of human rheumatoid arthritis (RA). In this study, we newly investigated whether LH2171 could relieve the severity of experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis (MS), which is an autoimmune disease, but develop the symptoms by different mechanisms from RA. In MS and EAE, main cause of the disease is the abnormality in CD4 T cell immunity, whereas in RA and CIA, is that in antibody-mediated immunity. The intraperitoneal administration of LH2171 significantly decreased the incidence and clinical score of EAE in mice. LH2171 also reduced the numbers of pathogenic immune cells, especially Th17 cells, in the spinal cord at the peak stage of disease severity. Interestingly, before the onset of EAE, LH2171 administration remarkably decreased the ratio of Th17 cells to CD4 T cells in the inguinal lymph nodes (LNs), where pathogenic immune cells are activated to infiltrate the central nervous system, including the spinal cord. Furthermore, the expression of interleukin (IL)-6, an inflammatory cytokine essential for Th17 differentiation, decreased in the LNs of LH2171-administered mice. Moreover, LH2171 significantly inhibited IL-6 production from both DC2.4 and RAW264.7 cells, model cell lines of antigen-presenting cells. These findings suggest that LH2171 might down-regulate IL-6 production and the subsequent Th17 differentiation and spinal cord infiltration, consequently alleviating EAE symptoms.
我们最近报道，SBT2171（LH2171）可抑制原代免疫细胞的增殖和炎性细胞因子产生，并减轻小鼠胶原诱导性关节炎（CIA），这是一种人类类风湿关节炎（RA）模型。在本研究中，我们新研究了LH2171是否能缓解实验性自身免疫性脑脊髓炎（EAE）的严重程度，EAE是一种多发性硬化症（MS）的小鼠模型，MS是一种自身免疫性疾病，但发病机制与RA不同。在MS和EAE中，疾病的主要原因是CD4 T细胞免疫异常，而在RA和CIA中，主要原因是抗体介导的免疫异常。腹腔注射LH2171可显著降低小鼠EAE的发病率和临床评分。LH2171还减少了疾病严重程度高峰期脊髓中致病性免疫细胞的数量，尤其是Th17细胞。有趣的是，在EAE发病前，给予LH2171可显著降低腹股沟淋巴结（LNs）中Th17细胞与CD4 T细胞的比例，致病性免疫细胞在此被激活并浸润包括脊髓在内的中枢神经系统。此外，在给予LH2171的小鼠的LNs中，炎性细胞因子白细胞介素（IL）-6（Th17分化所必需的）的表达降低。此外，LH2171显著抑制抗原呈递细胞的模型细胞系DC2.4和RAW264.7细胞产生IL-6。这些发现表明，LH2171可能下调IL-6的产生以及随后的Th17分化和脊髓浸润，从而减轻EAE症状。
