The Nuclear Orphan Receptor NR4A1 is Involved in the Apoptotic Pathway Induced by LPS and Simvastatin in RAW 264.7 Macrophages

Yong Chan Kim; Seok Bean Song; Sang Kyu Lee; Sang Min Park; Young Sang Kim

doi:10.4110/in.2014.14.2.116

The Nuclear Orphan Receptor NR4A1 is Involved in the Apoptotic Pathway Induced by LPS and Simvastatin in RAW 264.7 Macrophages

Immune Netw. 2014 Apr;14(2):116-22. doi: 10.4110/in.2014.14.2.116. Epub 2014 Apr 21.

Authors

Yong Chan Kim¹, Seok Bean Song¹, Sang Kyu Lee¹, Sang Min Park¹, Young Sang Kim¹

Affiliation

¹ Department of Biochemistry, College of Natural Sciences, Chungnam National University, Daejeon 305-764, Korea.

Abstract

Macrophage death plays a role in several physiological and inflammatory pathologies such as sepsis and arthritis. In our previous work, we showed that simvastatin triggers cell death in LPS-activated RAW 264.7 mouse macrophage cells through both caspase-dependent and independent apoptotic pathways. Here, we show that the nuclear orphan receptor NR4A1 is involved in a caspase-independent apoptotic process induced by LPS and simvastatin. Simvastatin-induced NR4A1 expression in RAW 264.7 macrophages and ectopic expression of a dominant-negative mutant form of NR4A1 effectively suppressed both DNA fragmentation and the disruption of mitochondrial membrane potential (MMP) during LPS- and simvastatin-induced apoptosis. Furthermore, apoptosis was accompanied by Bcl-2-associated X protein (Bax) translocation to the mitochondria. Our findings suggest that NR4A1 expression and mitochondrial translocation of Bax are related to simvastatin-induced apoptosis in LPS-activated RAW 264.7 macrophages.

Keywords: Apoptosis; LPS; Macrophages; NR4A1; Simvastatin.