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Cellular and Molecular Neurobiology

, Volume 36, Issue 5, pp 777–788 | Cite as

SMAD4 is Involved in the Development of Endotoxin Tolerance in Microglia

  • Xiaorong Liu
  • Yongwei Qin
  • Aihua Dai
  • Yu Zhang
  • Huaqing Xue
  • Haidan Ni
  • Lijian Han
  • Liang Zhu
  • Debin Yuan
  • Tao Tao
  • Maohong Cao
Original Research

Abstract

Initial exposure of macrophages to LPS induces hyporesponsiveness to a second challenge with LPS, a phenomenon termed LPS tolerance. Smad4 plays important roles in the induction of LPS tolerance. However, the function of Smad4 in microglia remains unknown. Here we show that expression of Smad4 was highly up-regulated in LPS-tolerized mouse cerebral cortex. Smad4 was mostly colocalized with microglia, rarely with neurons. Using a microglia cell line, BV2, we find that LPS activates endogenous Smad4, inducing its migration into the nucleus and increasing its expression. Smad4 significantly suppressed TLR-triggered production of proinflammatory cytokines (IL-6), increased anti-inflammatory cytokine in LPS-tolerized microglia. Moreover, IL-6 concentrations in culture supernatants after second LPS challenge are higher in SMAD4 small interfering RNA (siRNA) BV2 cells than control siRNA BV2 cells, indicating failure to induce tolerance in absence of Smad4 signaling. In our study, we conclude that both in vivo and in vitro, Smad4 signaling is required for maximal induction of endotoxin tolerance.

Keywords

Smad4 Microglia Endotoxin tolerance LPS 

Notes

Acknowledgments

This work was supported by the National Natural Scientific Foundation of China (Nos. 81202368, 81371299, and 81201252), a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

Compliance with Ethical Standards

Conflict of interest

No potential conflicts of interest were disclosed.

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Xiaorong Liu
    • 1
  • Yongwei Qin
    • 2
    • 3
  • Aihua Dai
    • 1
  • Yu Zhang
    • 1
  • Huaqing Xue
    • 2
  • Haidan Ni
    • 1
  • Lijian Han
    • 1
  • Liang Zhu
    • 1
  • Debin Yuan
    • 2
  • Tao Tao
    • 2
  • Maohong Cao
    • 1
  1. 1.Department of NeurologyAffiliated Hospital of Nantong UniversityNantongChina
  2. 2.Jiangsu Province Key Laboratory for Inflammation and Molecular Drug TargetMedical College of Nantong UniversityNantongChcina
  3. 3.Department of Pathogen BiologyMedical College of Nantong UniversityNantongChina

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