Suppression of the TRIF-dependent signaling pathway of Toll-like receptors by luteolin.
Toll-like receptors (TLRs) play important roles in induction of innate immune responses for both host defense against invading pathogens and wound healing after tissue injury. Since dysregulation of TLR-mediated immune responses is closely linked to many chronic diseases, modulation of TLR activation by small molecules may have therapeutic potential against such diseases. Expression of the majority of lipopolysaccharide-induced TLR4 target genes is mediated through a MyD88-independent (TRIF-dependent) signaling pathway. In order to evaluate the therapeutic potential of the flavonoid luteolin we examined its effect on TLR-stimulated signal transduction via the TRIF-dependent pathway. Luteolin suppressed activation of Interferon regulatory factor 3 (IRF3) and NFkappaB induced by TLR3 and TLR4 agonists resulting in the decreased expression of target genes such as TNF-alpha, IL-6, IL-12, IP-10, IFNbeta, CXCL9, and IL-27 in macrophages. Luteolin attenuated ligand-independent activation of IRF3 or NFkappaB induced by TLR4, TRIF, or TBK1, while it did not inhibit TLR oligomerization. Luteolin inhibited TBK1-kinase activity and IRF3 dimerization and phosphorylation, leading to the reduction of TBK1-dependent gene expression. Structural analogs of luteolin such as quercetin, chrysin, and eriodictyol also inhibited TBK1-kinase activity and TBK1-target gene expression. These results demonstrate that TBK1 is a novel target of anti-inflammatory flavonoids resulting in the down-regulation of the TRIF-dependent signaling pathway. These results suggest that the beneficial activities of these flavonoids against inflammatory diseases may be attributed to the modulation of TLR-mediated inflammatory responses.
Department of Life Science, Gwangju Institute of Science and Technology, Gwangju, 500-712, Republic of Korea.
Jun Kyung
JK
Lee
So Young
SY
Kim
Yoon Sun
YS
Kim
Won-Ha
WH
Lee
Daniel H
DH
Hwang
Joo Young
JY
Lee
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000493:pharmacokinetics*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018929:Cell Culture Techniques; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D047468:Immunoprecipitation; D047311:Luteolin / Q000737:chemistry / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D009573:Nitrites / Q000378:metabolism; D010957:Plasmids; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D014162:Transfection
D033942:Adaptor Proteins, Vesicular Transport; D000894:Anti-Inflammatory Agents, Non-Steroidal; D005419:Flavonoids; D047311:Luteolin; D009573:Nitrites; D017346:Protein Serine-Threonine Kinases; D051193:Toll-Like Receptors; C476286:Ticam1 protein, mouse; C470409:TICAM1 protein, human; C498588:Tbk1 protein, mouse; C403191:TBK1 protein, human