Contraction-induced interleukin-6 gene transcription in skeletal muscle is regulated by c-Jun terminal kinase/activator protein-1

Martin Whitham, M. H Stanley Chan, Martin Pal, Vance B. Matthews, Oja Prelovsek, Sebastian Lunke, Assam El-Osta, Hella Broenneke, Jens Alber, Jens C Bruning, F. Thomas Wunderlich, Graeme I. Lancaster, Mark A. Febbraio

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Abstract

Exercise increases the expression of the prototypical myokine IL-6, but the precise mechanism by which this occurs has yet to be identified. To mimic exercise conditions, C2C12 myotubes were mechanically stimulated via electrical pulse stimulation (EPS). We compared the responses of EPS with the pharmacological Ca2+ carrier calcimycin (A23187) because contraction induces marked increases in cytosolic Ca2+ levels or the classical IκB kinase/NFκB inflammatory response elicited by H 2O2. We demonstrate that, unlike H2O 2-stimulated increases in IL-6 mRNA, neither calcimycin- nor EPS-induced IL-6 mRNA expression is under the transcriptional control of NFκB. Rather, we show that EPS increased the phosphorylation of JNK and the reporter activity of the downstream transcription factor AP-1. Furthermore, JNK inhibition abolished the EPS-induced increase in IL-6 mRNA and protein expression. Finally, we observed an exercise-induced increase in both JNK phosphorylation and IL-6 mRNA expression in the skeletal muscles of mice after 30 min of treadmill running. Importantly, exercise did not increase IL-6 mRNA expression in skeletal muscle-specific JNK-deficient mice. These data identify a novel contraction-mediated transcriptional regulatory pathway for IL-6 in skeletal muscle.

Original languageEnglish
Pages (from-to)10771-10779
Number of pages9
JournalJournal of Biological Chemistry
Volume287
Issue number14
DOIs
Publication statusPublished - 30 Mar 2012
Externally publishedYes

Cite this

Whitham, M., Chan, M. H. S., Pal, M., Matthews, V. B., Prelovsek, O., Lunke, S., El-Osta, A., Broenneke, H., Alber, J., Bruning, J. C., Wunderlich, F. T., Lancaster, G. I., & Febbraio, M. A. (2012). Contraction-induced interleukin-6 gene transcription in skeletal muscle is regulated by c-Jun terminal kinase/activator protein-1. Journal of Biological Chemistry, 287(14), 10771-10779. https://doi.org/10.1074/jbc.M111.310581