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TSC1 controls IL-1β expression in macrophages via mTORC1-dependent C/EBPβ pathway

Cellular & Molecular Immunology volume 13, pages 640–650 (2016)Cite this article

Abstract

The tuberous sclerosis complex 1 (TSC1) is a tumor suppressor that inhibits the mammalian target of rapamycin (mTOR), which serves as a key regulator of inflammatory responses after bacterial stimulation in monocytes, macrophages, and primary dendritic cells. Previous studies have shown that TSC1 knockout (KO) macrophages produced increased inflammatory responses including tumor necrosis factor-α (TNF-α) and IL-12 to pro-inflammatory stimuli, but whether and how TSC1 regulates pro-IL-1β expression remains unclear. Here using a mouse model in which myeloid lineage-specific deletion of TSC1 leads to constitutive mTORC1 activation, we found that TSC1 deficiency resulted in impaired expression of pro-IL-1β in macrophages following lipopolysaccharide stimulation. Such decreased pro-IL-1β expression in TSC1 KO macrophages was rescued by reducing mTORC1 activity with rapamycin or deletion of mTOR. Rictor deficiency has no detectable effect on pro-IL-1β synthesis, suggesting that TSC1 positively controls pro-IL-1β expression through mTORC1 pathway. Moreover, mechanism studies suggest that mTORC1-mediated downregulation of the CCAAT enhancer-binding protein (C/EBPβ) critically contributes to the defective pro-IL-1β expression. Overall, these findings highlight a critical role of TSC1 in regulating innate immunity by control of the mTOR1-C/EBPβ pathway.

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Acknowledgements

The authors wish to thank Dr Chenming Sun, Dr Lina Sun, and Mr Steven Shao for their kind review of the manuscript. This work was supported by grants from the National Basic Research Program of China (2011CB710903, 2010CB945301, Yong Zhao), the National Natural Science Foundation of China for General and Key Programs (C81130055, C81072396, Yong Zhao), and the CAS/SAFEA International Partnership Program for Creative Research Teams (Yong Zhao).

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Author notes

  1. Tao Yang and Linnan Zhu: Tao Yang and Linnan Zhu contributed equally to this work as co-first authors.

  2. Dr Yong Zhao, Transplantation Biology Research Division, State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beichen West Road 1-5, Chaoyang District, Beijing 100101, China. E-mail: zhaoy@ioz.ac.cn

  3. Dr Wenjun Ding, College of Life Sciences, Graduate University of the Chinese Academy of Sciences, No. .19A YuQuan Road, Beijing 100049, China. E-mail: dingwj@gucas.ac.cn

Authors and Affiliations

  1. State Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China

    Tao Yang, Linnan Zhu, Jianxia Peng & Yong Zhao

  2. Division of Molecular Embryonic Development, State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China

    Yanhua Zhai

  3. School of Life Science, University of Chinese Academy of Sciences, Beijing, China

    Qingjie Zhao & Wenjun Ding

  4. Department of Physiology and Pathophysiology, National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences and School of Basic Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    Hongbing Zhang

  5. MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, China

    Zhongzhou Yang

  6. Key Laboratory of Human Diseases Comparative Medicine, Ministry of Health,

    Lianfeng Zhang

  7. Institute of Laboratory Animal Science, CAMS & PUMC, Beijing, China

    Lianfeng Zhang

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  1. Tao Yang
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Yang, T., Zhu, L., Zhai, Y. et al. TSC1 controls IL-1β expression in macrophages via mTORC1-dependent C/EBPβ pathway. Cell Mol Immunol 13, 640–650 (2016). https://doi.org/10.1038/cmi.2015.43

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