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miR-135b-5p inhibits LPS-induced TNFα production via silencing AMPK phosphatase Ppm1e

Ping Li1, Jian-Bo Fan2, Yanxia Gao1

  • 1Department of Emergency, The Second Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China.

Oncotarget
|October 30, 2016
PubMed

Insights

MicroRNA-135b-5p activates AMPK signaling by downregulating Ppm1e, suppressing inflammatory TNFα production. This pathway inhibits lipopolysaccharide-induced reactive oxygen species and NFκB activation in monocytes and macrophages.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Signaling

Background:

  • AMP-activated protein kinase (AMPK) activation can mitigate lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNFα) production, a key mediator of tissue damage.
  • MicroRNAs (miRNAs) are emerging regulators of cellular signaling pathways, including those involved in inflammation.

Purpose of the Study:

  • To investigate the role of microRNA-135b-5p (miR-135b-5p) in modulating AMPK signaling and its downstream effects on LPS-induced TNFα production in monocytes.
  • To elucidate the mechanism by which miR-135b-5p regulates AMPK activation and inflammatory responses.

Main Methods:

  • Forced expression of miR-135b-5p in human U937 and THP-1 monocyte cell lines.
  • Downregulation of Ppm1e (phosphatase, prolyl-rich, EF-hand motif containing 1) using miR-135b-5p mimic or shRNA.
  • Assessment of AMPK signaling activation via Western blot.
  • Measurement of LPS-induced TNFα production using ELISA.
  • Inhibition of AMPK signaling using shRNA or dominant-negative mutation.
  • Evaluation of reactive oxygen species (ROS) production, NFκB activation, and TNFα mRNA expression in macrophages.

Main Results:

  • Forced expression of miR-135b-5p downregulated Ppm1e and activated AMPK signaling in monocytes.
  • miR-135b-5p significantly attenuated LPS-induced TNFα production.
  • Knockdown of Ppm1e using shRNA also activated AMPK and inhibited TNFα production.
  • AMPK activation was essential for miR-135b-5p's inhibitory effects on TNFα production.
  • miR-135b-5p suppressed LPS-induced ROS production, NFκB activation, and TNFα mRNA expression in macrophages, effects dependent on AMPK activation.

Conclusions:

  • miR-135b-5p activates AMPK signaling by downregulating Ppm1e.
  • This miR-135b-5p-mediated AMPK activation effectively inhibits LPS-induced TNFα production in monocytes and macrophages.
  • The mechanism involves the suppression of ROS production and NFκB activation.
Keywords:
AMPKLPSPpm1eTNFαmiR-135b-5p

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