Open AccessSTAT 3 promotes IFN γ/ TNF α‐induced muscle wasting in an NF ‐κB‐dependent and IL ‐6‐independent manner
Author(s) -
Ma Jennifer F,
Sanchez Brenda J,
Hall Derek T,
Tremblay AnneMarie K,
Di Marco Sergio,
Gallouzi ImedEddine
Publication year - 2017
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201607052
Subject(s) - stat , chemistry , wasting , tumor necrosis factor alpha , microbiology and biotechnology , cytokine , signal transduction , biology , immunology , biochemistry , stat3
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, IFN γ, and TNF α is well established, we still do not know how various effector pathways collaborate together to trigger muscle atrophy. Here, we show that IFN γ/ TNF α promotes the phosphorylation of STAT 3 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 STAT 3‐mediated muscle wasting. pY ‐ STAT 3 forms a complex with NF ‐κB that is rapidly imported to the nucleus where it is recruited to the promoter of the iN os gene to activate the iNOS / NO pathway, a well‐known downstream effector of IFN γ/ TNF α‐induced muscle loss. Together, these findings show that STAT 3 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.