Wang Jianyong, Shao Yu, Bennett Teri A, Shankar Raji A, Wightman Paul D, Reddy Laxma G
Department of Pharmacology, 3M Pharmaceutical Division, St. Paul, Minnesota 55144, USA.
J Biol Chem. 2006 Dec 8;281(49):37427-34. doi: 10.1074/jbc.M605311200. Epub 2006 Oct 13.
Toll-like receptors (TLRs) TLR1, TLR2, TLR4, and TLR6 are evolutionarily conserved, highly homologous, and localized to plasma membranes of host cells and recognize pathogen-associated molecular patterns (PAMPs) derived from bacterial membranes. These receptors cooperate in a pairwise combination to elicit or inhibit the inflammatory signals in response to certain PAMPs. The other TLRs that are evolutionarily closely related and highly homologous are TLR7, TLR8, and TLR9. They are all confined to the membranes of endosomes and recognize similar molecular structures, the oligonucleotide-based PAMPs. However, the cooperative interactions among these receptors that may modulate the inflammatory signaling in response to their cognate agonists are not reported. We report here for the first time the functional effects of one TLR on the other among TLR7, TLR8, and TLR9. The results indicate that TLR8 inhibits TLR7 and TLR9, and TLR9 inhibits TLR7 but not vice versa in HEK293 cells transfected with TLRs in a pairwise combination. This is concluded by selectively activating one TLR over the other by using small molecule TLR agonists. We also show that these inhibitory interactions are the result of direct or indirect physical interactions between the TLRs. The murine TLR8 that does not respond to any known human TLR8 agonists also inhibits both murine and human TLR7. The implications of the inhibitory interactions among these TLRs in host-pathogen recognition and subsequent inflammatory responses are not obvious. However, given the complexity in expression pattern in a particular cell type and the variation in distribution and response to different pathogens and stress signals in different cell types, the inhibitory physical interactions among these TLRs may play a role in balancing the inflammatory outcome from a given cell type to a specific challenge.
Toll样受体（TLRs）中的TLR1、TLR2、TLR4和TLR6在进化上保守、高度同源，定位于宿主细胞的质膜，识别源自细菌膜的病原体相关分子模式（PAMPs）。这些受体以两两组合的方式协同作用，以响应某些PAMPs引发或抑制炎症信号。在进化上密切相关且高度同源的其他TLRs是TLR7、TLR8和TLR9。它们都局限于内体膜，识别类似的分子结构，即基于寡核苷酸的PAMPs。然而，尚未报道这些受体之间可能调节对其同源激动剂的炎症信号传导的协同相互作用。我们在此首次报道了TLR7、TLR8和TLR9中一种TLR对另一种TLR的功能影响。结果表明，在以两两组合方式转染了TLRs的HEK293细胞中，TLR8抑制TLR7和TLR9，TLR9抑制TLR7，但反之则不然。这是通过使用小分子TLR激动剂选择性激活一种TLR而不是另一种TLR得出的结论。我们还表明，这些抑制性相互作用是TLRs之间直接或间接物理相互作用的结果。对任何已知人类TLR8激动剂均无反应的小鼠TLR8也抑制小鼠和人类TLR7。这些TLRs之间抑制性相互作用在宿主-病原体识别及随后炎症反应中的意义尚不明确。然而，鉴于特定细胞类型中表达模式的复杂性以及不同细胞类型中对不同病原体和应激信号的分布及反应的差异，这些TLRs之间的抑制性物理相互作用可能在平衡特定细胞类型对特定挑战的炎症反应结果中发挥作用。
