Toll-like receptor 9-mediated inhibition of apoptosis occurs through suppression of FoxO3a activity and induction of FLIP expression

Synthetic oligodeoxynucleotides (ODN) with a CpG-motif are recognized by Toll-like receptor 9 (TLR9) and pleiotropic immune responses are elicited. Stimulation of macrophages with TLR9 agonist prevented apoptosis induced by serum deprivation through increased expression of FLICE-like inhibitory protein (FLIP). CpG ODN-mediated anti-apoptosis depended on the TLR9-Akt-FoxO3a signaling pathway. Inhibition of TLR9 by small interfering (si) RNA or an inhibitor suppressed CpG ODN-mediated anti-apoptosis. Analysis of signaling pathways revealed that the anti-apoptotic effect of CpG ODN required phosphorylation of FoxO3a and its translocation from the nucleus to the cytosol. Overexpression of FoxO3a increased apoptosis induced by serum deprivation and CpG ODN blocked these effects through FLIP expression. In contrast, siRNA knock-down of FoxO3a decreased apoptosis by serum deprivation. In addition, Akt activation was involved in CpG ODN-induced phosphorylation of FoxO3a, expression of FLIP, and anti-apoptosis. Taken together, these results demonstrate the involvement of Akt-FoxO3a in TLR9-mediated anti-apoptosis and indicate that FoxO3a is a distinct regulator for FLIP expression.

Tuberous Sclerosis Manifested by Spontaneous Rupture of Renal Angiomyolipoma in a Patient with Polycystic Kidney Disease / 대한신장학회지

Tuberous sclerosis is an autosomal dominant disorder characterized by seizure, mental retardation and harmatomatous lesions in multiple organs. The renal lesions of tuberous sclerosis are multiple angiomyolipomas often associated with cysts of various sizes. A 47-year-old man who had been on hemodialysis for 12 years was admitted to our hospital because of sudden onset of right flank pain. He had polycystic kidney disease and adenoma sebaceum. Abdominal computed tomography showed an enlarged right kidney with massive hemorrhage, and renal arteriography showed massive bleeding. Immediate transarterial embolization and radical nephrectomy on the right kidney was done. Pathologic examination revealed ruptured renal angiomyolipoma, confirming that he had contiguous gene syndrome. We experienced a case of tuberous sclerosis with spontaneous rupture of renal angiomyolipoma in a hemodialysis patient with autosomal dominant polycystic kidney disease.

Arsenic Trioxide Induces A poptosis in Human Colorectal Adenocarcinoma HT-29 Cells Through ROS / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Treatment with arsenic trioxide (As2O3) results in a wide range of cellular effects that includes induction of apoptosis, inhibition of cell growth, promotion or inhibition of cellular differentiation, and inhibition of angiogenesis through a variety of mechanisms. The mechanisms of As2O3-induced cell death have been mainly studied in hematological cancers, and those mechanisms in solid cancers have yet to be clearly defined. In this study, the mechanisms by which As2O3 induces apoptosis in human colorectal adenocarcinoma HT-29 cells were investigated. MATERIALS AND METHODS: To examine the levels of apoptosis, HT-29 cells were treated with As2O3 and then we measured the percentage of Annexin V binding cells, the amount of ROS production and the mitochondrial membrane potential. Western blot analysis was performe to identify the activated caspases after As2O3 exposure, and we compared the possible target molecules of apoptosis. As2O3 treatment induced the loss of the mitochondrial membrane potential and an increase of ROS, as well as activation of caspase-3, -7, -9 and -10. RESULTS: As2O3 induced apoptosis via the production of reactive oxygen species and the loss of the mitochondrial membrane potential. As2O3 induced the activation of caspase-3, -7, -9 and -10. Furthermore, As2O3 treatment downregulates the Mcl-1 and Bcl-2 expressions, and the release of cytochrome c and an apoptosis-inducing factor (AIF). Pretreating the HT-29 cells with N-acetyl-L-cysteine, which is a thiol-containing antioxidant, inhibited the As2O3- Induced Apoptosis and Caspase Activation. CONCLUSION: Taken together, these results suggest that the generation of reactive oxygen species (ROS) by As2O3 might play an important role in the regulation of As2O3-induced apoptosis. This cytotoxicity is mediated through a mitochondria-dependent apoptotic signal pathway in HT-29 cells.