RRC ID 58856
著者 Yabuta S, Shidoji Y.
タイトル TLR4-mediated pyroptosis in human hepatoma-derived HuH-7 cells induced by a branched-chain polyunsaturated fatty acid, geranylgeranoic acid.
ジャーナル Biosci Rep
Abstract A branched-chain polyunsaturated fatty acid, geranylgeranoic acid (GGA; C20:4), which is an endogenous metabolite derived from the mevalonate pathway in mammals, has been reported to induce cell death in human hepatoma cells. We have previously shown that the lipid-induced unfolded protein response (UPR) is an upstream cellular process for an incomplete autophagic response that might be involved in GGA-induced cell death. Here, we found that Toll-like receptor 4 (TLR4)-mediated pyroptosis in HuH-7 cells occurred by GGA treatment. The TLR4-specific inhibitor VIPER prevented both GGA-induced cell death and UPR. Knockdown of the TLR4 gene attenuated GGA-induced cell death significantly. Upon GGA-induced UPR, caspase (CASP) 4 (CASP4) was activated immediately and gasdermin D (GSDMD) was translocated concomitantly to the plasma membrane after production of the N-terminal fragment of GSDMD. Then, cellular CASP1 activation occurred following a second gradual up-regulation of the intracellular Ca2+ concentration, suggesting that GGA activated the inflammasome. Indeed, the mRNA levels of NOD-like receptor family pyrin domain containing 3 (NLRP3) and interleukin-1 β (IL1B) genes were up-regulated dramatically with translocation of cytoplasmic nuclear factor-κB (NF-κB) to nuclei after GGA treatment, indicating that GGA induced priming of the NLRP3 inflammasome through NF-κB activation. GGA-induced up-regulation of CASP1 activity was blocked by either oleic acid, VIPER, MCC950 (a selective inhibitor of the NLRP3 inflammasome), or CASP4-specific inhibitor peptide cotreatment. Pyroptotic cell death was also confirmed morphologically by bleb formation in time-series live cell imaging of GGA-treated cells. Taken together, the present results strongly indicate that GGA causes pyroptotic cell death in human hepatoma-derived HuH-7 via TLR4 signalling.
巻・号 40(4)
公開日 2020-4-30
DOI 10.1042/BSR20194118
PII 222621
PMID 32270855
PMC PMC7189495
MeSH Carcinoma, Hepatocellular / drug therapy* Carcinoma, Hepatocellular / pathology Cell Line, Tumor Diterpenes / pharmacology* Diterpenes / therapeutic use Gene Knockdown Techniques Humans Liver Neoplasms / drug therapy* Liver Neoplasms / pathology Pyroptosis / drug effects* Toll-Like Receptor 4 / antagonists & inhibitors Toll-Like Receptor 4 / genetics Toll-Like Receptor 4 / metabolism* Unfolded Protein Response / drug effects
IF 2.942
引用数 0
リソース情報
ヒト・動物細胞 HuH-7