Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10816337 | Cellular Signalling | 2005 | 10 Pages |
Abstract
Wasting of skeletal muscle (cachexia) is associated with a variety of chronic or inflammatory disorders and has long been recognized as a poor prognostic sign. It is currently accepted that the cytokine tumor necrosis factor alpha (TNF-α; cachectin) plays a key role in the development of this condition. TNF-α-induced apoptotic cell death represents a potential mechanism by which muscle wasting can occur. Evidence has accumulated that the cytokine interferon gamma (IFN-γ) may act as a modulator of TNF-α signalling. Thus, the present study was designed to elucidate if TNF-α can directly induce apoptosis in differentiated myotubes, to assess the potential anti-apoptotic properties of IFN-γ and to get insight into the signalling pathways implicated in the modulatory effects of IFN-γ. Myoblasts of the murine cell line C2C12 were allowed to differentiate in a low serum containing media and myogenesis assessed by muscle specific protein expression. Non-proliferating, polynucleated, fully differentiated myotubes were obtained after seven days in differentiation media. Exposure of C2C12 myotubes to TNF-α for 48 h induced apoptosis characterized by enhanced caspase-3 activity, which resulted in poly(ADP-ribose) polymerase (PARP) cleavage and increased histone-associated-DNA fragmentation. These effects were fully reverted in the presence of IFN-γ. This cytokine induced down-regulation of the subtype 2 of TNF-α receptors (TNF-R2), enhanced TNF-α-induced NF-κB translocation to the nucleus and binding to DNA and increased the immunoreactivity of the protein c-IAP1, a member of the inhibitor of apoptosis (IAP) gene family whose synthesis is stimulated by NF-κB at the transcriptional level. Together, these results demonstrate that TNF-α directly induces apoptosis in differentiated myotubes and suggest that the cytokine IFN-γ, might represent a new immunoadjuvant therapeutic tool for managing cachexia.
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Authors
Laia Tolosa, Montse Morlá, Amanda Iglesias, Xavier Busquets, Jerònia Lladó, Gabriel Olmos,