24(S)-Hydroxycholesterol induces RIPK1-dependent but MLKL-independent cell death in the absence of caspase-8.

Abstract

24(S)-Hydroxycholesterol (24S-OHC), which is enzymatically produced in the brain, is known to play an important role in maintaining brain cholesterol homeostasis. We have previously reported that 24S-OHC induces a type of non-apoptotic programmed necrosis in neuronal cells expressing little caspase-8. Necroptosis has been characterized as a type of programmed necrosis in which activation of receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like (MLKL) is involved in the signaling pathway. In the present study, we investigated the involvement of these three proteins in 24S-OHC-induced cell death. We found that RIPK1 but neither RIPK3 nor MLKL was expressed in human neuroblastoma SH-SY5Y cells, while all three proteins were expressed in human T lymphoma caspase-8-deficient Jurkat (Jurkat(Cas8-/-)) cells. In Jurkat(Cas8-/-) cells, tumor necrosis factor α (TNFα)-induced cell death was significantly suppressed by treatment with respective inhibitors of RIPK1, RIPK3, and MLKL. In contrast, only RIPK1 inhibitor showed significant suppression of 24S-OHC-induced cell death, and even this was less prominent than was observed in TNFα-induced cell death. In Jurkat(Cas8-/-) cells, knockdown of either RIPK1 or RIPK3 caused moderate but significant suppression of 24S-OHC-induced cell death, but no such effect was observed as a result of knockdown of MLKL. Collectively, these results suggest that, for both SH-SY5Y cells and Jurkat(Cas8-/-) cells, 24S-OHC-induced cell death is dependent on RIPK1 but not on MLKL. We therefore conclude that, in the absence of caspase-8 activity, 24S-OHC induces a necroptosis-like cell death which is RIPK1-dependent but MLKL-independent.

• Authors: Diep-Khanh Ho Vo, Yasuomi Urano, Wakako Takabe, Yoshiro Saito, Noriko Noguchi
• Journal: Steroids (Steroids) Vol. 99 Issue Pt B Pg. 230-7 (Jul 2015) ISSN: 1878-5867 [Electronic] United States
• PMID: 25697054 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Hydroxycholesterols
• Protein Kinase Inhibitors
• 24-hydroxycholesterol
• MLKL protein, human
• Protein Kinases
• RIPK1 protein, human
• RIPK3 protein, human
• Receptor-Interacting Protein Serine-Threonine Kinases
• CASP8 protein, human
• Caspase 8

Topics

• Caspase 8 (metabolism)
• Cell Death (drug effects)
• Cell Line, Tumor
• Gene Knockdown Techniques
• Humans
• Hydroxycholesterols (pharmacology)
• Models, Biological
• Protein Kinase Inhibitors (pharmacology)
• Protein Kinases (metabolism)
• Receptor-Interacting Protein Serine-Threonine Kinases (metabolism)