| First Author | Zhou J | Year | 2023 |
| Journal | Int Immunopharmacol | Volume | 122 |
| Pages | 110574 | PubMed ID | 37421775 |
| Mgi Jnum | J:338855 | Mgi Id | MGI:7513674 |
| Doi | 10.1016/j.intimp.2023.110574 | Citation | Zhou J, et al. (2023) Heat stress-induced intestinal epithelial cells necroptosis via TLR3-TRIF-RIP3 pathway was dependent on p53. Int Immunopharmacol 122:110574 |
| abstractText | BACKGROUND: Heatstroke is a life-threatening disease. Present study was aimed to investigate the mechanism in heat induced intestinal epithelial cell death. METHOD: Heat stress in vitro model was established on IEC cells with 42 for 2 h. Caspase-8 inhibitor, Caspase-3 inhibitor, RIP3 inhibitor, TLR3 agonist, poly(I:C) and p53 knockdown were used to determine the signaling pathway. Heatstroke in vivo model was established on C57BL/6 mice, with a temperature of 35.5+/-0.5 and a relative humidity of 60% +/- 5%. The intestine necroptosis and inflammatory cytokines were measured. Pifithrin alpha (3 mg/kg) and p53 knockout mice were used to evaluate the role of p53. RESULTS: Heat stress-induced reduction of cell viability was remarkable reversed by RIP3 inhibitor. Heat stress induced upregulation of TLR3 and facilitate the formation of TRIF-RIP3 complex. The heat stress induced upregulation of RIP3 and p-RIP3 were normalized by the deletion of p53. Meanwhile, p53 knockout decreased TLR3 expression and blocked the formation of TLR3-TRIF complex. The deletion of p53 blocked the decreased cell viability and restored the activation of RIP3-MLKL signaling after heat stress, however, which were abolished by re-expression of p53 via Tp53 OE. Increased the expression of TLR3 in the p53-deficient cells could not affect the heat stress induced necrotic cell death, which suggests that heat stress induced necroptosis via TLR3-TRIF-RIP3 signaling pathway is dependent on p53. CONCLUSION: Heat stress promoted p53 phosphorylation, then upregulated TLR3 and enhanced the interaction of TRIF-RIP3, which would activate the RIP3-MLKL signaling pathway to mediate necroptosis in intestinal epithelial cells. |
