TLR4-MyD88-TRAF6-TAK1 Complex-Mediated NF-κB Activation Contribute to the Anti-Inflammatory Effect of V8 in LPS-Induced Human Cervical Cancer SiHa Cells.
The synthetic compound 7-4-[Bis-(2-hydroxyethyl)-amino]-butoxy-5-hydroxy-8-methoxy-2-phenylchromen-4-one (V8) is a novel flavonoid-derived compound. In this study, we investigated the effects of V8 on Toll-like receptor 4 (TLR4)-mediated inflammatory reaction in human cervical cancer SiHa cells and lipopolysaccharide (LPS)-induced TLR4 activity in cervical cancer SiHa (HPV16+) cells, but not in HeLa (HPV18+) and C33A (HPV-) cells. In addition, V8 inhibited LPS-induced expression of TLR4, MyD88, TRAF6 and phosphorylation of TAK1, and their interaction with TLR4 in SiHa cells, resulting in an inhibition of TLR4-MyD88-TRAF6-TAK1 complex. Moreover, V8 blocked LPS-induced phosphorylation of IκB and IKK, resulting in inhibition of the nuclear translocation of P65-NF-κB in SiHa cells. We also found that V8 reduced the expression of NF-κB target genes, such as those for COX-2, iNOS, IL-6, IL-8, CCL-2, and TNF-α in LPS-stimulated SiHa cells. These results suggested that V8 exerted an anti-inflammatory effect on SiHa cells by inhibiting the TLR4-MyD88-TRAF6-TAK1 complex-mediated NF-κB activation.
Department of Gynecology Oncology, Nantong Tumor Hospital, Tumor Hospital Affiliated to Nantong University, Nantong, China. heaiqinnantong@163.com.
Aiqin
A
He
Department of Gynecology Oncology, Nantong Tumor Hospital, Tumor Hospital Affiliated to Nantong University, Nantong, China.
Rui
R
Ji
Department of Gynecology Oncology, Nantong Tumor Hospital, Tumor Hospital Affiliated to Nantong University, Nantong, China.
Jia
J
Shao
Department of Gynecology Oncology, Nantong Tumor Hospital, Tumor Hospital Affiliated to Nantong University, Nantong, China.
Chenyun
C
He
Department of Gynecology Oncology, Nantong Tumor Hospital, Tumor Hospital Affiliated to Nantong University, Nantong, China.
Ming
M
Jin
Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, China. xuyunzhaonantong@163.com.
Yunzhao
Y
Xu
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005260:Female; D047309:Flavones / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D010766:Phosphorylation / Q000187:drug effects; D048029:TNF Receptor-Associated Factor 6 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D051996:Transcription Factor RelA / Q000378:metabolism; D002583:Uterine Cervical Neoplasms; D000099151:MAP Kinase Kinase Kinase 7
D000893:Anti-Inflammatory Agents; D047309:Flavones; D005419:Flavonoids; D051550:I-kappa B Kinase; D008070:Lipopolysaccharides; D020930:MAP Kinase Kinase Kinases; D053594:Myeloid Differentiation Factor 88; D048029:TNF Receptor-Associated Factor 6; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; D000099151:MAP Kinase Kinase Kinase 7; C000592659:7-(4-(bis-(2-hydroxyethyl)amino)butoxy)-5-hydroxy-8-methoxy-2-phenylchromen-4-one; C507779:MYD88 protein, human; C498143:RELA protein, human; C495345:TLR4 protein, human
HPV16; NF-κB; TLR4; V8; cervical cancer; inflammation