Oosting Marije, Cheng Shih-Chin, Bolscher Judith M, Vestering-Stenger Rachel, Plantinga Theo S, Verschueren Ineke C, Arts Peer, Garritsen Anja, van Eenennaam Hans, Sturm Patrick, Kullberg Bart-Jan, Hoischen Alexander, Adema Gosse J, van der Meer Jos W M, Netea Mihai G, Joosten Leo A B
Department of Internal Medicine.
Department of Immune Therapeutics, Merck Research Laboratories, Oss 5342 CC, The Netherlands.
Proc Natl Acad Sci U S A. 2014 Oct 21;111(42):E4478-84. doi: 10.1073/pnas.1410293111. Epub 2014 Oct 6.
Toll-like receptor (TLR)10 is the only pattern-recognition receptor without known ligand specificity and biological function. We demonstrate that TLR10 is a modulatory receptor with mainly inhibitory effects. Blocking TLR10 by antagonistic antibodies enhanced proinflammatory cytokine production, including IL-1β, specifically after exposure to TLR2 ligands. Blocking TLR10 after stimulation of peripheral blood mononuclear cells with pam3CSK4 (Pam3Cys) led to production of 2,065 ± 106 pg/mL IL-1β (mean ± SEM) in comparison with 1,043 ± 51 pg/mL IL-1β after addition of nonspecific IgG antibodies. Several mechanisms mediate the modulatory effects of TLR10: on the one hand, cotransfection in human cell lines showed that TLR10 acts as an inhibitory receptor when forming heterodimers with TLR2; on the other hand, cross-linking experiments showed specific induction of the anti-inflammatory cytokine IL-1 receptor antagonist (IL-1Ra, 16 ± 1.7 ng/mL, mean ± SEM). After cross-linking anti-TLR10 antibody, no production of IL-1β and other proinflammatory cytokines could be found. Furthermore, individuals bearing TLR10 polymorphisms displayed an increased capacity to produce IL-1β, TNF-α, and IL-6 upon ligation of TLR2, in a gene-dose-dependent manner. The modulatory effects of TLR10 are complex, involving at least several mechanisms: there is competition for ligands or for the formation of heterodimer receptors with TLR2, as well as PI3K/Akt-mediated induction of the anti-inflammatory cytokine IL-1Ra. Finally, transgenic mice expressing human TLR10 produced fewer cytokines when challenged with a TLR2 agonist. In conclusion, to our knowledge we demonstrate for the first time that TLR10 is a modulatory pattern-recognition receptor with mainly inhibitory properties.
Toll样受体（TLR）10是唯一一种配体特异性和生物学功能尚不明确的模式识别受体。我们证明TLR10是一种主要具有抑制作用的调节性受体。用拮抗抗体阻断TLR10可增强促炎细胞因子的产生，包括IL-1β，特别是在暴露于TLR2配体后。用Pam3CSK4（Pam3Cys）刺激外周血单个核细胞后阻断TLR10，可导致IL-1β产生量为2,065±106 pg/mL（平均值±标准误），而添加非特异性IgG抗体后IL-1β产生量为1,043±51 pg/mL。TLR10的调节作用由多种机制介导：一方面，在人细胞系中共转染显示，TLR10与TLR2形成异二聚体时作为抑制性受体发挥作用；另一方面，交联实验显示抗炎细胞因子IL-1受体拮抗剂（IL-1Ra，16±1.7 ng/mL，平均值±标准误）有特异性诱导。交联抗TLR10抗体后，未发现IL-1β和其他促炎细胞因子的产生。此外，携带TLR10多态性的个体在TLR2被激活后，以基因剂量依赖的方式产生IL-1β、TNF-α和IL-6的能力增强。TLR10的调节作用很复杂，至少涉及几种机制：存在对配体的竞争或与TLR2形成异二聚体受体方面的竞争，以及PI3K/Akt介导的抗炎细胞因子IL-1Ra的诱导。最后，用TLR2激动剂攻击时，表达人TLR10的转基因小鼠产生的细胞因子较少。总之，据我们所知，我们首次证明TLR10是一种主要具有抑制特性的调节性模式识别受体。
