Tumor necrosis factor-alpha exerts interleukin-6-dependent and -independent effects on cultured skeletal muscle cells

Biochim Biophys Acta. 2002 Jan 30;1542(1-3):66-72. doi: 10.1016/s0167-4889(01)00167-7.


In vivo studies have shown that cancer-associated skeletal muscle wasting (cachexia) is mediated by two cytokines, tumor necrosis factor-alpha (TNF) and interleukin-6 (IL-6). It has been unclear from these studies whether TNF exerts direct effects on skeletal muscle and/or whether these effects are mediated via IL-6. Previous studies from our laboratory have shown that TNF induces IL-6 mRNA expression in cultured skeletal muscle cells. To further investigate the relationship between TNF and IL-6, the effects of TNF and IL-6 on protein and DNA dynamics in murine C2C12 skeletal myotube cultures were determined. At 1000 U/ml, TNF induced 30% increases in protein and DNA content. The effects of TNF on protein accumulation were inhibited by aphidicolin, an inhibitor of DNA synthesis. IL-6 mimicked the effects of TNF on C2C12 cultures, inducing a 32% increase in protein accumulation and a 71% increase in the rate of protein synthesis. IL-6 also decreased expression of mRNA for several proteolytic system components, including ubiquitin 2.4 kb (51%) and 1.2 kb (63%), cathepsin B (39%) and m-calpain (47%), indicating that IL-6 acts on both protein synthesis and degradation. Incubation of murine C2C12 myotube cultures with TNF (1000 U/ml) in the presence of a polyclonal mouse anti-IL-6 antibody resulted in an abolishment of the effects of TNF on protein synthesis, but did not inhibit TNF-induced stimulation of DNA synthesis. These findings indicate that the effects of TNF on muscle protein synthesis are mediated by IL-6, but that TNF exerts IL-6-independent effects on proliferation of murine skeletal myoblasts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Division / drug effects
  • Cells, Cultured
  • Interleukin-6 / biosynthesis
  • Interleukin-6 / metabolism*
  • Interleukin-6 / pharmacology
  • Mice
  • Muscle Proteins / biosynthesis
  • Muscle Proteins / genetics
  • Muscle, Skeletal / drug effects*
  • Muscle, Skeletal / metabolism
  • RNA, Messenger / analysis
  • Time Factors
  • Tumor Necrosis Factor-alpha / pharmacology*


  • Interleukin-6
  • Muscle Proteins
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha