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

Jennifer F. Ma, Brenda J. Sanchez, Derek T. Hall, Anne Marie K Tremblay, Sergio Di Marco, Imed Gallouzi

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Cachexia is a debilitating syndrome characterized by involuntary muscle wasting that is triggered at the late stage of many cancers. While the multifactorial nature of this syndrome and the implication of cytokines such as IL-6, IFNγ, and TNFα is well established, we still do not know how various effector pathways collaborate together to trigger muscle atrophy. Here, we show that IFNγ/TNFα promotes the phosphorylation of STAT3 on Y705 residue in the cytoplasm of muscle fibers by activating JAK kinases. Unexpectedly, this effect occurs both in vitro and in vivo independently of IL-6, which is considered as one of the main triggers of STAT3-mediated muscle wasting. pY-STAT3 forms a complex with NF-κB that is rapidly imported to the nucleus where it is recruited to the promoter of the iNos gene to activate the iNOS/NO pathway, a well-known downstream effector of IFNγ/TNFα-induced muscle loss. Together, these findings show that STAT3 and NF-κB respond to the same upstream signal and cooperate to promote the expression of pro-cachectic genes, the identification of which could provide effective targets to combat this deadly syndrome.

Original languageEnglish
JournalEMBO Molecular Medicine
DOIs
Publication statusAccepted/In press - 2017
Externally publishedYes

Fingerprint

Interleukin-6
Muscles
Janus Kinases
Cachexia
Muscular Atrophy
Genes
Smooth Muscle
Cytoplasm
Phosphorylation
Cytokines
Neoplasms
In Vitro Techniques

Keywords

  • iNOS
  • Inflammation
  • Muscle wasting
  • NF-κB
  • STAT3

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

STAT3 promotes IFNγ/TNFα-induced muscle wasting in an NF-κB-dependent and IL-6-independent manner. / Ma, Jennifer F.; Sanchez, Brenda J.; Hall, Derek T.; Tremblay, Anne Marie K; Di Marco, Sergio; Gallouzi, Imed.

In: EMBO Molecular Medicine, 2017.

Research output: Contribution to journalArticle

Ma, Jennifer F. ; Sanchez, Brenda J. ; Hall, Derek T. ; Tremblay, Anne Marie K ; Di Marco, Sergio ; Gallouzi, Imed. / STAT3 promotes IFNγ/TNFα-induced muscle wasting in an NF-κB-dependent and IL-6-independent manner. In: EMBO Molecular Medicine. 2017.
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