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MUSCLE CELL BIOLOGY AND CELL MOTILITY

Upregulation of IL-6 mRNA by IL-6 in skeletal muscle cells: role of IL-6 mRNA stabilization and Ca²⁺-dependent mechanisms

¹Department of Internal Medicine, Division of Endocrinology, Metabolism, Pathobiochemistry, and Clinical Chemistry, ²Department of Pharmacology, Institute of Pharmacy, and ³Division of Sports Medicine, Medical Clinic, University of Tuebingen, Tuebingen, Germany

Submitted 5 April 2007 ; accepted in final form 2 July 2007

Skeletal muscle cells have been established as significant producers of IL-6 during exercise. This IL-6 production is discussed as one possible mediator of the beneficial effects of physical activity on glucose and fatty acid metabolism. IL-6 itself could be the exercise-related factor that upregulates and maintains its own production. We investigated this hypothesis and the underlying molecular mechanism in cultured C₂C₁₂ cells. IL-6 led to a rapid and prolonged increase in IL-6 mRNA, which was also found in human myotubes. Because IL-6 has been shown to activate AMP-activated kinase (AMPK), we studied whether, in turn, activated AMPK induces IL-6 expression. Pharmacological activation of AMPK with 5-aminoimidazole-4-carboxamide-1--4-ribofuranoside upregulated IL-6 mRNA expression, which was blocked by knockdown of AMPK ₁ and ₂ using small, interfering RNA (siRNA) oligonucleotides. However, the effect of IL-6 was shown to be independent of AMPK, since the siRNA approach silencing the AMPK -subunits did not reduce the upregulation of IL-6 induced by IL-6 stimulation. The self-stimulatory effect of IL-6 partly involves a Ca²⁺-dependent pathway: IL-6 increased intracellular Ca²⁺, and intracellular blockade of Ca²⁺ with a Ca²⁺ chelator reduced the IL-6-mediated increase in IL-6 mRNA levels. Moreover, inhibition of Ca²⁺/calmodulin-dependent kinase kinase with STO-609 or the siRNA approach decreased IL-6 mRNA levels of control and IL-6-stimulated cells. A major, STO-609-independent mechanism is the IL-6-mediated stabilization of its mRNA. The data suggest that IL-6 could act as autocrine factor upregulating its mRNA levels, thereby supporting its function as an exercise-activated factor in skeletal muscle cells.

5-aminoimidazole-4-carboxamide-1--4-ribofuranoside; AMP-activated kinase; STO-609; calcium/calmodulin-dependent kinase kinase; C₂C₁₂ cells

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