HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 293/3/C1139    most recent 00142.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (11) Citing Articles via Google Scholar Google Scholar Articles by Weigert, C. Articles by Schleicher, E. D. Search for Related Content PubMed PubMed Citation Articles by Weigert, C. Articles by Schleicher, E. D.

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

This article has been cited by other articles:

				N. Ichinoseki-Sekine, H. Naito, K. Tsuchihara, I. Kobayashi, Y. Ogura, R. Kakigi, M. Kurosaka, R. Fujioka, and H. Esumi Provision of a voluntary exercise environment enhances running activity and prevents obesity in Snark-deficient mice Am J Physiol Endocrinol Metab, May 1, 2009; 296(5): E1013 - E1021. [Abstract] [Full Text] [PDF]

				B. M. Meador, C. P. Krzyszton, R. W. Johnson, and K. A. Huey Effects of IL-10 and age on IL-6, IL-1{beta}, and TNF-{alpha} responses in mouse skeletal and cardiac muscle to an acute inflammatory insult J Appl Physiol, April 1, 2008; 104(4): 991 - 997. [Abstract] [Full Text] [PDF]