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A novel TLR2‐triggered signalling crosstalk synergistically intensifies TNF‐mediated IL‐6 induction |
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| Authors: | Yu‐Ling Chang Tzu‐Hui Chen Yi‐Hsiu Wu Guann‐An Chen Tzu‐Huei Weng Ping‐Hui Tseng Shie‐Liang Hsieh Shu‐Ling Fu Chi‐Hung Lin Chun‐Jen Chen Ching‐Liang Chu Iok In Christine Chio Tak Wah Mak Nien‐Jung Chen |
| Affiliation: | 1. Institute of Microbiology and Immunology, School of Life Sciences, National Yang‐Ming University, , Taipei, Taiwan;2. Institute of Biochemistry and Molecular Biology, School of Life Sciences, National Yang‐Ming University, , Taipei, Taiwan;3. Inflammation and Immunity Research Center, National Yang‐Ming University, , Taipei, Taiwan;4. Institute of Clinical Medicine, School of Medicine, National Yang‐Ming University, , Taipei, Taiwan;5. Genomics Research Center, Academia Sinica, , Taipei, Taiwan;6. Institute for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Immunology Center, Taipei Veterans General Hospital, , Taipei, Taiwan;7. Institute of Traditional Medicine, School of Medicine, National Yang‐Ming University, , Taipei, Taiwan;8. Department of Biochemical Science and Technology, College of Life Science, National Taiwan University, , Taipei, Taiwan;9. Graduate Institute of Immunology, College of Medicine, National Taiwan University, , Taipei, Taiwan;10. The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, University Health Network and Department of Medical Biophysics, University of Toronto, , Toronto, ON, Canada |
| Abstract: | Toll‐like receptors (TLR) recognize pathogens and trigger the production of vigorous pro‐inflammatory cytokines [such as tumour necrosis factor (TNF)] that induce systemic damages associated with sepsis and chronic inflammation. Cooperation between signals of TLR and TNF receptor has been demonstrated through the participation of TNF receptor 1 (TNFR) adaptors in endotoxin tolerance. Here, we identify a TLR2‐mediated synergy, through a MyD88‐independent crosstalk, which enhances subsequent TNF‐mediated nuclear factor‐kappa B activation and interleukin‐6 induction. Membrane‐associated adaptor MAL conduces the link between TNF receptor‐associated factor 6 (TRAF6) and TNFR‐associated death domain, leading to a distinctive K63‐ubiquitinylated TRAF6 recruitment into TNFR complex. In summary, our results reveal a novel route of TLR signal that synergistically amplifies TNF‐mediated responses, indicating an innovative target for inflammation manipulation. |
| Keywords: | Toll‐like receptor tumour necrosis factor signalling crosstalk TRAF6 TRADD |