title: Contraction-induced interleukin-6 gene transcription in skeletal muscle is regulated by c-Jun terminal kinase/activator protein-1.
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 Ca(2+) carrier calcimycin (A23187) because contraction induces marked increases in cytosolic Ca(2+) levels or the classical IκB kinase/NFκB inflammatory response elicited by H(2)O(2). We demonstrate that, unlike H(2)O(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.
authors.affiliation: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 8008, Australia.
authors.forename: Martin
authors.initials: M
authors.lastname: Whitham
authors.forename: M H Stanley
authors.initials: MH
authors.lastname: Chan
authors.forename: Martin
authors.initials: M
authors.lastname: Pal
authors.forename: Vance B
authors.initials: VB
authors.lastname: Matthews
authors.forename: Oja
authors.initials: O
authors.lastname: Prelovsek
authors.forename: Sebastian
authors.initials: S
authors.lastname: Lunke
authors.forename: Assam
authors.initials: A
authors.lastname: El-Osta
authors.forename: Hella
authors.initials: H
authors.lastname: Broenneke
authors.forename: Jens
authors.initials: J
authors.lastname: Alber
authors.forename: Jens C
authors.initials: JC
authors.lastname: Brüning
authors.forename: F Thomas
authors.initials: FT
authors.lastname: Wunderlich
authors.forename: Graeme I
authors.initials: GI
authors.lastname: Lancaster
authors.forename: Mark A
authors.initials: MA
authors.lastname: Febbraio
mesh_terms: D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002460:Cell Line; D004558:Electric Stimulation; D015850:Interleukin-6 / Q000235:genetics*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000201:enzymology / Q000378:metabolism* / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D015850:Interleukin-6; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D000001:Calcimycin; D048031:JNK Mitogen-Activated Protein Kinases