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STAT3 promotes IFNγ/TNFα-induced muscle wasting in an NF-κB-dependent and IL-6-independent manner

Jennifer F Ma1, Brenda J Sanchez1, Derek T Hall1

  • 1Department of Biochemistry, Rosalind and Morris Goodman Cancer Centre, McGill University, Montreal, QC, Canada.

EMBO Molecular Medicine
|March 8, 2017
PubMed

Insights

Interferon gamma (IFNγ) and Tumor Necrosis Factor alpha (TNFα) activate STAT3 independently of Interleukin-6 (IL-6), revealing a new pathway in cancer cachexia.

Area of Science:

  • Oncology
  • Molecular Biology
  • Physiology

Background:

  • Cachexia is a complex syndrome of involuntary muscle wasting in late-stage cancer.
  • Cytokines like IL-6, IFNγ, and TNFα are implicated, but their collaborative mechanisms in muscle atrophy are unclear.

Purpose of the Study:

  • To investigate the collaborative roles of IFNγ, TNFα, and IL-6 in STAT3-mediated muscle wasting.
  • To elucidate the molecular pathways linking these cytokines to muscle atrophy.

Main Methods:

  • In vitro and in vivo studies were conducted.
  • Investigated the phosphorylation of STAT3 and its interaction with NF-κB.
  • Analyzed the activation of the iNOS/NO pathway.

Main Results:

  • IFNγ/TNFα activate JAK kinases, leading to STAT3 phosphorylation at Y705 in muscle fibers, independent of IL-6.
  • Phosphorylated STAT3 (pY-STAT3) forms a complex with NF-κB.
  • This complex is imported into the nucleus, activating the iNOS gene and the iNOS/NO pathway.

Conclusions:

  • STAT3 and NF-κB collaborate in response to IFNγ/TNFα signaling.
  • This cooperation promotes the expression of pro-cachectic genes, offering potential therapeutic targets.
  • Identifies a novel IL-6-independent mechanism in cancer cachexia pathogenesis.
Keywords:
iNOSNF‐κBSTAT3inflammationmuscle wasting

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