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SIRT1 suppresses activator protein-1 transcriptional activity and cyclooxygenase-2 expression in macrophages

Ran Zhang1, Hou-Zao Chen, Jin-Jing Liu

  • 1National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China.

The Journal of Biological Chemistry
|January 1, 2010
PubMed

Insights

Calorie restriction (CR) enhances macrophage function by upregulating SIRT1 (Sirtuin type 1). SIRT1 deacetylates and suppresses activator protein-1 (AP-1), reducing COX-2 expression and improving immune responses.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Immunology

Background:

  • Sirtuin type 1 (SIRT1) is a key mediator of calorie restriction (CR)-induced physiological changes.
  • The role of SIRT1 in regulating activator protein-1 (AP-1) and its downstream effects on macrophage function remains unclear.

Purpose of the Study:

  • To investigate whether SIRT1 deacetylates AP-1 and influences its transcriptional activity.
  • To determine the impact of SIRT1 on AP-1 target gene expression, specifically COX-2, in macrophages.
  • To elucidate the role of SIRT1 in CR-mediated regulation of macrophage function.

Main Methods:

  • Direct interaction assays between SIRT1, c-Fos, and c-Jun.
  • Measurement of AP-1 transcriptional activity.
  • Analysis of COX-2 expression and prostaglandin E(2) (PGE(2)) production in peritoneal macrophages (pMPhis).
  • Assessment of macrophage phagocytosis and tumoricidal functions.
  • Studies involving SIRT1 overexpression and deacetylase inhibition in macrophages from CR mice.

Main Results:

  • SIRT1 directly interacts with c-Fos and c-Jun, suppressing AP-1 transcriptional activity via its deacetylase function.
  • SIRT1 reduces COX-2 expression and PGE(2) production in pMPhis.
  • SIRT1 overexpression enhances pMPhis phagocytosis and tumoricidal functions, linked to decreased PGE(2).
  • CR upregulates SIRT1 in mouse pMPhis, leading to reduced COX-2 and improved macrophage functions, effects reversed by SIRT1 inhibition.

Conclusions:

  • SIRT1 acts as a crucial mediator of CR-induced macrophage regulation.
  • SIRT1's deacetylase activity inhibits AP-1 transcriptional activity and COX-2 expression.
  • These mechanisms contribute to the amelioration of macrophage function under calorie restriction.

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