Endocrine Abstracts (2007) 13 P123

Controversial interactions between TNF-alpha and IL-6 in C2 skeletal myoblast cell death

Nasser Al-Shanti, Amarjit Saini & Claire Stewart

Department of Exercise and Sport Science, Institute for Biophysical and Clinical Research into Human Movement, Manchester Metropolitan University, Alsager-Stoke On Trent, United Kingdom.

Introduction: The role of TNF-alpha in muscle wasting diseases if a topic of great interest. However, the role of interleukin-6 (IL-6) in some pathological diseases and in skeletal muscle is controversial. Physical exercise provides protection against several human diseases, e.g. cardiovascular disease, heart failure and claudicatio intermittens. This protection is associated with the muscle specific production of IL-6. In contrast to its protective role during exercise, elevated levels of IL-6 are reported in several diseases, e.g. cancer cachexia, multiple myeloma, elderly chronic inflammation and in growth deficient children and is believed to be detrimental in the context of skeletal muscle.

Aims: To investigate the controversial role of IL-6 in skeletal myoblasts, and to manipulate its interaction with TNF-α.

Methods: Murine skeletal muscle cells (C2 myoblasts) were used as our model to investigate temporal IL-6 and TNF-α interactions. Upon attaining 80% confluency in 20% serum, cells were transferred to 2% serum-containing differentiation medium (DM). Cells were cultured in the absence or presence of TNF (10 ng/ml). IL-6 (2.5 ng/ml) was additionally administrated 1, 2, 4, 6 and 24hrs following the transfer into DM. Cells were harvested at 48 h, (24 hrs following the last IL-6 dose) to examine the cell growth and death interactions of IL-6/TNF-α.

Results: In the absence of IL-6, TNF-α (10 ng/ml) induced significant cell death vs. DM alone (P<0.05) while IL-6 alone was without effect on cell death, although high doses (10 ng/ml) did block differentiation. When the cells were cultured with TNF-α in the presence of IL-6, the ability of TNF-α to induce cell death was blocked. Indeed, the capacity of IL-6 to negate the effects of TNF increased with time, with cell survival gradually increasing throughout the culture period of 48hrs. The viable cell count increased by 20±3% (P<0.05) compared to the cell count when IL-6 was added at 1hr. The ability of IL-6 to reduce the effects of TNF-alpha appears to involve MAPK activation, since addition of the MAP kinase inhibitor (PD98059 20 μmole) to our co-cultures demolished the ability of IL-6 to prevent TNF-induced cell death.

Conclusions: These observations support that data that IL-6 blocks the ability of TNF-α to induce skeletal muscle cell death and may therefore be a fundamental cytokine for preserving satellite cell numbers and therefore ensuring skeletal muscle homeostasis.

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