A novel TLR2-triggered signalling crosstalk synergistically intensifies TNF-mediated IL-6 induction

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


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.

Original languageEnglish
Pages (from-to)1344-1357
Number of pages14
JournalJournal of Cellular and Molecular Medicine
Issue number7
StatePublished - Jul 2014


  • Signalling crosstalk
  • TRAF6
  • Toll-like receptor
  • Tumour necrosis factor


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