Stress sensors of skeletal muscle: heat shock-induced cytokine expression . Focus on “Skeletal muscle interleukin-6 regulation in hyperthermia”
2013; American Physical Society; Volume: 305; Issue: 4 Linguagem: Inglês
10.1152/ajpcell.00184.2013
ISSN1522-1563
Autores Tópico(s)Heat shock proteins research
ResumoEditorial FocusStress sensors of skeletal muscle: heat shock-induced cytokine expression. Focus on "Skeletal muscle interleukin-6 regulation in hyperthermia"Philip M. GallagherPhilip M. GallagherApplied Physiology Laboratory, Department of Health, Sport and Exercise Sciences, University of Kansas, Lawrence, KansasPublished Online:15 Aug 2013https://doi.org/10.1152/ajpcell.00184.2013This is the final version - click for previous versionMoreSectionsPDF (286 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat traditionally, the drastic increase in circulating IL-6 and other cytokines seen during exercise was thought to originate from mononuclear cells associated with the general inflammatory response. Activation of the IKK/NF-κB pathway associated with inflammation would lead to the production of IL-6 and other cytokines (1). However, more recent data have shown that IL-6 expression remains unchanged or even decreases in monocytes during exercise (9). Furthermore, studies as early as the late 1990s have shown that many tissue types, including skeletal muscle, produce cytokines (6). The increase in IL-6 expression in skeletal muscle occurs fairly rapidly upon the start of exercise and can increase 100-fold during prolonged physical activity. Thus, the role of skeletal muscle is being considered more broadly to include its function as a pseudo-endocrine organ.The mechanisms of increased IL-6 expression, however, have not yet been fully elucidated. There are drastic intra- and extracellular environmental changes that occur during contractions and exercise, and these alterations give rise to numerous potential pathways of IL-6 expression. Changes in calcium, reactive oxygen species (ROS), cellular energy levels, hormones, and temperature may initiate the expression of IL-6 (Fig. 1). Many studies have shown that increases in calcium and the Ca2+ ionophore ionomycin result in increased IL-6 expression. However, the exact mechanism of calcium-induced IL-6 expression is unresolved. Early studies suggested that calcium-induced expression of IL-6 occurred via the calcineurin/NFAT pathway. More recent data have shown a fiber-type-specific expression of IL-6 in fast-twitch fibers, implying that calcium-induced expression of IL-6 most likely occurs through a different, but unknown, pathway (2). Thus, the specific pathways for calcium-induced IL-6 expression may be different in slow- and fast-twitch fibers. Exercise has also been shown to significantly increase the production of ROS in skeletal muscle as a result of oxidative stress during exercise. This increase in ROS may not just be toxic to cells, but may trigger intracellular pathways, including pathways that upregulate cytokine production. The ROS-induced expression of IL-6 most likely occurs by means of the JNK/p38(MAPK)/activator protein-1 (AP-1) pathway (4). Furthermore, low glycogen levels have been found to increase IL-6 expression, suggesting that a low energy status of muscle cells may trigger cytokine production (3).Fig. 1.Simplified diagram of IL-6 transcriptional regulation in skeletal muscle. ROS, reactive oxygen species; ER stress/UPR, endoplasmic reticulum stress/unfolded protein response.Download figureDownload PowerPointIn this issue of the American Journal of Physiology-Cell Physiology, Welc et al. (12) from Dr. Clanton's laboratory have presented interesting data on the mechanisms of IL-6 expression in response to hyperthermic conditions. These researchers found that both heat shock factor-1 (HSF-1) and AP-1 play major roles in hyperthermic induction of IL-6 in C2C12 cells. An earlier study by these researchers showed that IL-6 levels increases 1,000-fold two hours following heat shock in mice (11). In addition to molecular chaperones (heat shock proteins) that protect, fold, or unfold proteins, hyperthermia induces the expression of numerous genes associated with cellular repair (general review, 8). Many of these genes are associated with apoptosis and protein degradation, cell cycle, and cytokine production. The role that the transcription factor HSF-1 has in gene regulation in response to hyperthermia has been well documented, especially in reference to the expression of heat shock proteins. HSF-1 is rapidly activated during elevated temperatures by trimerization and that allows it to bind to the heat shock element (HSE) promoter sequence (7). In the previous study by Welc et al. (11), it was shown that the inhibition of HSF-1 with KNK437 during heat shock prevented IL-6 transcription in skeletal muscle cells. As a follow-up to that study, these researchers utilized a luciferase reporter plasmid under transcriptional control of the mouse IL-6 promoter in muscle myotubes that were then allowed to differentiate. Under hyperthermic conditions, IL-6 promoter activity increased over 150%. Additional studies were performed to show the vital role that HSF-1 and AP-1 have in regulating IL-6 transcription in response to hyperthermic environments.Certain cellular responses to heat shock may not actually be due to increased temperature, but may be due to the endoplasmic reticulum stress signaling, also known as the unfolded protein response (UPR) (10). However, prior to the study profiled in this edition of American Journal of Physiology-Cell Physiology by Welc et al. (12), it has yet be determined whether the UPR regulates IL-6 expression in skeletal muscle. In this study they showed an increase in IL-6 secreted from C2C12 cells exposed to four different nonspecific pharmacological agents known to induce the UPR. Further research in this area is needed as a possible target for the treatment of muscle-related diseases and disorders.The role that muscle-derived IL-6 plays in the body is somewhat controversial (5). IL-6 has both pro- and anti-inflammatory properties. IL-6 has been associated with muscle atrophy and cachexia and has been shown to inhibit the expression of other proinflammatory cytokines in skeletal muscle. The fact that HSF-1 and AP-1 are required for IL-6 expression in skeletal muscle suggests that the role of IL-6 associated with the heat shock and stress response may be undervalued. IL-6 plays an important part in the inhibition of protein synthesis, in increased protein degradation, and in the inhibition of apoptosis. Thus, increased IL-6 expression during hyperthermia may be a vital approach that cells employ to manage heat stress and support survival.GRANTSThis study was sponsored, in part, by a University of Kansas School of Education General Research Fund grant.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the author.AUTHOR CONTRIBUTIONSP.M.G. prepared figure; drafted manuscript; edited and revised manuscript; approved final version of manuscript.REFERENCES1. Brack A, Rittner HL, Younge BR, Kaltschmidt C, Weyand CM, Goronzy JJ. Glucocorticoid-mediated repression of cytokine gene transcription in human arteritis-SCID chimeras. J Clin Invest 99: 2842–50, 1997.Crossref | PubMed | ISI | Google Scholar2. Hiscock N, Chan MS, Bisucci T, Darby IA, Febbraio MA. Skeletal myocytes are a source of interleukin-6 mRNA expression and protein release during contraction: evidence of fiber type specificity. FASEB J 18: 992–994, 2004.Crossref | PubMed | ISI | Google Scholar3. 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Peteranderl R, Nelson HC. Trimerization of the heat shock transcription factor by a triple-stranded alpha-helical coiled-coil. Biochemistry 31: 12272–12276, 1992.Crossref | PubMed | ISI | Google Scholar8. Sonna LA, Fujita J, Gaffin SL, Lilly CM. Invited review: effects of heat and cold stress on mammalian gene expression. J Appl Physiol 92: 1725–1742, 2002.Link | ISI | Google Scholar9. Starkie RL, Rolland J, Angus DJ, Anderson MJ, Febbraio MA. Circulating monocytes are not the source of elevations in plasma IL-6 and TNF-α levels after prolonged running. Am J Physiol Cell Physiol 280: C769–C774, 2001.Link | ISI | Google Scholar10. Travers KJ, Patil CK, Wodicka L, Lockhart DJ, Weissman JS, Walter P. Functional and genomic analyses reveal an essential coordination between the unfolded protein response and ER-associated degradation. Cell 101: 249–258, 2000.Crossref | PubMed | ISI | Google Scholar11. Welc SS, Phillips NA, Oca-Cossio J, Wallet SM, Chen DL, Clanton TL. Hyperthermia increases interleukin-6 in mouse skeletal muscle. Am J Physiol Cell Physiol 303: C455–C466, 2012.Link | ISI | Google Scholar12. Welc SS, Judge AR, Clanton TL. Skeletal muscle interleukin-6 regulation in hyperthermia. Am J Physiol Cell Physiol (May 1, 2013). doi:10.1152/ajpcell.00084.2013.Link | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: P. M. Gallagher, Applied Physiology Laboratory, Dept. of Health, Sport and Exercise Sciences, Univ. of Kansas, Lawrence, KS 66045 (e-mail: philku@ku.edu). Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited ByThe Signaling Network Resulting in Ventilator-induced Diaphragm DysfunctionAmerican Journal of Respiratory Cell and Molecular Biology, Vol. 59, No. 4Short-Wave Diathermy Pretreatment and Inflammatory Myokine Response After High-Intensity Eccentric ExerciseJournal of Athletic Training, Vol. 50, No. 6Skeletal muscle interleukin-6 regulation in hyperthermiaSteven S. Welc, Andrew R. Judge, and Thomas L. Clanton15 August 2013 | American Journal of Physiology-Cell Physiology, Vol. 305, No. 4 More from this issue > Volume 305Issue 4August 2013Pages C375-C376 Copyright & PermissionsCopyright © 2013 the American Physiological Societyhttps://doi.org/10.1152/ajpcell.00184.2013PubMed23784546History Published online 15 August 2013 Published in print 15 August 2013 Metrics
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