Beschreibung:
<jats:p>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 C<jats:sub>2</jats:sub>C<jats:sub>12</jats:sub>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-β-4-ribofuranoside upregulated IL-6 mRNA expression, which was blocked by knockdown of AMPK α<jats:sub>1</jats:sub>and α<jats:sub>2</jats:sub>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 α-subunits did not reduce the upregulation of IL-6 induced by IL-6 stimulation. The self-stimulatory effect of IL-6 partly involves a Ca<jats:sup>2+</jats:sup>-dependent pathway: IL-6 increased intracellular Ca<jats:sup>2+</jats:sup>, and intracellular blockade of Ca<jats:sup>2+</jats:sup>with a Ca<jats:sup>2+</jats:sup>chelator reduced the IL-6-mediated increase in IL-6 mRNA levels. Moreover, inhibition of Ca<jats:sup>2+</jats:sup>/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.</jats:p>