Interferon-Gamma Is A Potent Activator Of Caspase 12 In C2c12 Cells Hl112085, Hl113494
FASEB JOURNAL(2015)
Abstract
We recently found that pharmacologic activation of endoplasmic reticulum (ER) stress in vivo induces skeletal muscle contractile dysfunction. However, it is not known if cytokines are capable of inducing ER stress in muscle. The purpose of the present study was to determine if interferon gamma (IFNγ), tumor necrosis factor alpha (TNFα), or interleukin1 beta (IL1β) activates ER stress and the unfolded protein response (UPR) in skeletal muscle. C2C12 myoblasts were grown to 80% confluence, differentiated for 5 days, and mature myotubes exposed to either PBS+0.1% BSA (control), IFNγ (25ng/ml),TNFα (20ng/ml), or IL1β (10ng/ml). Cells were harvested at 30 minutes, 1, 2, 4, 8, and 24 hours post‐exposure (n=5/condition/time point). Using Western blots, we assessed cleavage of caspase 12, an early marker of ER stress; we also measured BiP, Grp94, calreticulin, PDI and CHOP, proteins which are late markers of ER stress and the UPR. At 24 hours after exposure, caspase 12 cleavage robustly increased in C2C12 cells exposed to IFNγ, while TNFα and IL1β had little effect to activate caspase 12 (e.g. the 38 kDa caspase 12 degradation product increased 7‐fold with IFNγ, when compared to control, TNFα , or IL1β, p<0.001). We did not detect significant changes in late markers of ER stress at 24 hours. Our findings indicate that IFNγ is a potent activator of ER stress in skeletal muscle. Future studies are needed to determine the role of IFNγ –mediated ER stress activation in clinical conditions which produce skeletal muscle dysfunction (e.g. sepsis, cancer, and aging).
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Key words
c2c12 cells,interferon‐γ,caspase
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