Tsukamoto Hiroki, Yamagata Yuki, Ukai Ippo, Takeuchi Shino, Okubo Misaki, Kobayashi Yohei, Kozakai Sao, Kubota Kanae, Numasaki Muneo, Kanemitsu Yoshitomi, Matsumoto Yotaro, Tomioka Yoshihisa
Laboratory of Oncology, Pharmacy Practice and Sciences, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
Department of Geriatrics and Gerontology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
FEBS Lett. 2017 Aug;591(16):2406-2416. doi: 10.1002/1873-3468.12768. Epub 2017 Aug 8.
Lipopolysaccharide (LPS)-induced activation of Toll-like receptor 4 (TLR4) elicits the innate immune response and can trigger septic shock if excessive. Two antibodies (HT4 and HT52) inhibit LPS-induced human TLR4 activation via novel LPS binding-independent mechanisms. The HT52 epitope resides on leucine-rich repeat 2 (LRR2) and is a feature of many inhibitory antibodies; antigen specificity of HT4 does not reside in LRR2. Here, we identified an HT4 epitope on LRR13 located close to the TLR4 dimerization interface that plays a role in NFκB activation. HT4 and HT52 mutually enhanced TLR4 inhibition. LRR13 is a novel inhibitory epitope and may be useful for developing anti-TLR4 antibodies. Combination therapy with LRR2 and LRR13 may effectively inhibit TLR4 activation.
脂多糖（LPS）诱导的Toll样受体4（TLR4）激活引发先天免疫反应，如果过度激活则可引发脓毒性休克。两种抗体（HT4和HT52）通过新的不依赖LPS结合的机制抑制LPS诱导的人TLR4激活。HT52表位位于富含亮氨酸重复序列2（LRR2）上，是许多抑制性抗体的一个特征；HT4的抗原特异性并不存在于LRR2中。在这里，我们在靠近TLR4二聚化界面的LRR13上鉴定出一个HT4表位，该表位在NFκB激活中发挥作用。HT4和HT52相互增强对TLR4的抑制作用。LRR13是一个新的抑制性表位，可能有助于开发抗TLR4抗体。LRR2和LRR13联合治疗可能有效抑制TLR4激活。
