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.
Institute of Microbiology and Immunology, School of Life Sciences, National Yang-Ming University, Taipei, Taiwan.
Yu-Ling
YL
Chang
Tzu-Hui
TH
Chen
Yi-Hsiu
YH
Wu
Guann-An
GA
Chen
Tzu-Huei
TH
Weng
Ping-Hui
PH
Tseng
Shie-Liang
SL
Hsieh
Shu-Ling
SL
Fu
Chi-Hung
CH
Lin
Chun-Jen
CJ
Chen
Ching-Liang
CL
Chu
Iok In Christine
II
Chio
Tak Wah
TW
Mak
Nien-Jung
NJ
Chen
D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D047468:Immunoprecipitation; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053199:TNF Receptor-Associated Death Domain Protein / Q000502:physiology*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D016207:Cytokines; D015850:Interleukin-6; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D012333:RNA, Messenger; D053199:TNF Receptor-Associated Death Domain Protein; D051195:Toll-Like Receptor 2; C481226:Tradd protein, mouse; D014409:Tumor Necrosis Factor-alpha
TRADD; TRAF6; Toll-like receptor; signalling crosstalk; tumour necrosis factor