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

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.
Mesh Terms:
Animals, Blotting, Western, Cells, Cultured, Cytokines, Gene Expression Regulation, Humans, Immunoprecipitation, Inflammation, Interleukin-6, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Differentiation Factor 88, NF-kappa B, RNA, Messenger, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, TNF Receptor-Associated Death Domain Protein, Toll-Like Receptor 2, Tumor Necrosis Factor-alpha
J. Cell. Mol. Med.
Date: Jul. 01, 2014
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