Clock-controlled StAR’s expression and corticosterone production contribute to the endotoxemia immune response

Abstract

Increased studies have revealed that core mammalian clock genes regulate immune functions. Previously, we reported Per2^m/m mice displayed a down-regulated circadian immune response to lipopolysaccharide (LPS) challenge. However, the mediators between Per2 and immune function and their underlying mechanisms remain unclear. In this study, serum corticosterone (CORT), a hormone which played a crucial role in immune suppression, was found to be significantly increased in Per2^m/m mice compared with the one in wild-type mice following LPS administration at ZT3 and ZT8. The elevated level of serum CORT was correlated with their higher survival rate, which could be further suppressed by glucocorticoid receptor antagonist. Expression of StAR, a rate-limiting enzyme in CORT synthesis, as well as the expression of core clock genes (Clock/Bmal1), was more strongly induced and longer lasting in Per2^m/m mice in contrast to the ones in control mice after LPS injection. Additionally, the binding of CLOCK and BMAL1 to StAR’s promoter was elevated after LPS administration, and the binding was higher in Per2^m/m mice. Furthermore, loss of Clock function resulted in lower survival and failed to induce the serum CORT production and StAR expression in Clock^m/m mice following LPS administration. Our results revealed that CORT, regulated by Bmal1/Clock transcriptional activation of StAR’s expression, could function as a mediator between clock system and immune response and contribute to the endotoxemia resistance in Per2^m/m mice.

• Circadian clock
• corticosterone
• endotoxemia
• lipopolysaccharide
• Per2
• StAR

Acknowledgements

We thank Dr. Xiaozhong Peng (Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Beijing, China) for generously providing the pcDNA4-Myc-hClock and pcDNA4-Myc-hBMal1 plasmids, and Dr. Ying Xu (Model Animal Research Center of Nanjing University, Nanjing, China) for providing Clock^m/m mice.

Declaration of interest

This work was supported by grants from National Natural Science Foundation of China (31200888, 31271266 and 30770786). The authors report no conflicts of interest.

Supplementary information available online

Supplementary Table 1 and Figure 1