Korean Journal of Clinical Laboratory Science (대한임상검사과학회지)

Korean Society for Clinical Laboratory Science (대한임상검사과학회)
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Caspase-8 Potentiates Triglyceride (TG)-Induced Cell Death of THP-1 Macrophages via a Positive Feedback Loop

Caspase-8의 양성 피드백 방식을 통한 중성지방-유도 THP-1 대식세포 사멸 증가

  • Jung, Byung Chul (Department of Nutritional Sciences and Toxicology, University of California) ;
  • Lim, Jaewon (Department of Biomedical Laboratory Science, College of Software and Digital Healthcare Convergence, Yonsei University) ;
  • Kim, Sung Hoon (Department of Biomedical Laboratory Science, College of Software and Digital Healthcare Convergence, Yonsei University) ;
  • Kim, Yoon Suk (Department of Biomedical Laboratory Science, College of Software and Digital Healthcare Convergence, Yonsei University)
  • 정병출 (캘리포니아대학교 버클리캠퍼스 영양과학 및 독성학과) ;
  • 임재원 (연세대학교 소프트웨어디지털헬스케어융합대학 임상병리학과) ;
  • 김성훈 (연세대학교 소프트웨어디지털헬스케어융합대학 임상병리학과) ;
  • 김윤석 (연세대학교 소프트웨어디지털헬스케어융합대학 임상병리학과)
  • Received : 2021.02.25
  • Accepted : 2021.04.13
  • Published : 2021.06.30
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Abstract

Hypertriglyceridemia is the main risk factor for atherosclerosis. It is reported that triglyceride (TG) induces macrophage cell death, and is involved in the formation of plaques and development of atherosclerosis. We previously reported that TG-induced cell death of macrophages is mediated via pannexin-1 activation, which increases the extracellular ATP and subsequent increase in potassium efflux, thereby activating the caspase-2/caspase-1/apoptotic caspases, including the caspase-8 pathway. Contrarily, some studies have reported that caspase-8 is an upstream molecule of caspase-1 and caspase-2 in several cellular processes. Therefore, this study was undertaken to investigate whether caspase-8 influences its upstream molecules in TG-stimulated macrophage cell death. We first confirmed that caspase-8 induces caspase-3 activation and poly ADP-ribose polymerase (PARP) cleavage in TG-treated macrophages. Next, we determined that the inhibition of caspase-8 results in reduced caspase-1 and -2 activity, which are upstream molecules of caspase-8 in TG-induced cell death of macrophages. We also found that ATP treatment restores the caspase-8 inhibitor-induced caspase-2 activity, thereby implying that caspase-8 affects the upstream molecules responsible for increasing the extracellular ATP levels in TG-induced macrophage cell death. Taken together, these findings indicate that caspase-8 potentiates the TG-induced macrophage cell death by activating its upstream molecules.

고중성지방혈증은 죽상동맥경화증의 주요한 위험 요인 중 하나이다. 중성지방은 대식세포의 세포 사멸을 유도하여 죽상동맥경화증 발생에 기여하는 것으로 알려져 있다. 본 연구팀은 앞선 연구에서 대식세포의 중성지방-유도 세포 사멸이 pannexin-1 활성화에 의한 세포 외 ATP 농도 증가, caspase-2와 caspase-1 활성화, caspase-8을 포함한 apoptotic caspase 활성화 경로로 일어나는 것을 보고하였다. 한편 다른 연구들에서는 세포 내 다른 여러 기전에서 caspase-8이 caspase-1과 -2의 상위 단백질이라 보고하고 있다. 따라서 본 연구에서는 caspase-8이 중성지방-유도 대식세포 사멸 과정에서 상위단백지로 영향을 미치는지 여부를 조사하기 위해 수행되었다. 본 연구진은 caspase-8이 중성지방-유도 대식세포 사멸 과정에서 caspase-3 활성화 및 PARP 절단을 유도하였다. 다음으로 중성지방이 처리된 대식세포에서 caspase-8 억제 시, caspase-8의 상위 단백질로 보고한 caspase-1 및 -2의 활성이 감소하는 것을 확인하였다. 또한 ATP 처리 시 caspase-8 억제제 처리에 의해 감소된 caspase-2의 활성이 회복되는 것을 확인하였다. 위의 결과를 통해 caspase-8이 중성지방-유도 대식세포 사멸 과정에서 세포 외부 ATP 농도 증가에 관여하는 단백질 또는 그 상위 기전에 양성피드백 방식으로 영향을 미쳐 caspase-1과 -2를 활성화하여 중성지방-유도 대식세포 사멸을 증진시킴을 알 수 있다.

Keywords

Acknowledgement

This Research was supported by the Korea Nazarene University Research Grants 2021.

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