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Lipoic Acid Exerts Antioxidant and Anti-inflammatory Effects in Response to Heat Shock in C2C12 Myotubes

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Abstract

This study explored that lipoic acid treatment for 24 h significantly upregulated and promoted heat shock-induced catalase expression and downregulated GPx1 messenger RNA (mRNA) expression, indicating that lipoic acid exhibits antioxidant activity in the decomposition of hydrogen peroxide by upregulating catalase expression. Moreover, lipoic acid treatment for 3 h increased and promoted heat shock-induced interleukin (IL)-6 mRNA and protein levels and that for 24 h downregulated IL-6 mRNA expression, suggesting a dual effect of lipoic acid on IL-6 regulation. Lipoic acid alone failed to increase or reduce tumor necrosis factor (TNF)-α mRNA and protein levels, whereas heat shock alone downregulated TNF-α mRNA and protein expression. These data suggest that lipoic acid does not have a proinflammatory role and that heat shock acts as an anti-inflammatory agent by downregulating TNF-α expression in C2C12 myotubes. Moreover, lipoic acid or heat shock alone upregulated the IL-6 receptor (IL-6R-α) and glycoprotein 130 (gp130) mRNA expression followed by IL-6 expression; these data indicate that the regulation of lipoic acid or heat shock is mediated by IL-6R signaling, thus suggesting that C2C12 myotubes possesses a mechanism for regulating IL-6R and gp130 expression following lipoic acid treatment or heat shock.

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REFERENCES

  1. Akerfelt, M., R.I. Morimoto, and L. Sistonen. 2010. Heat shock factors: integrators of cell stress, development and lifespan. Nature Reviews Molecular Cell Biology 11: 545–555.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Demarco, V.G., P.O. Scumpia, J.P. Bosanquet, and J.W. Skimming. 2004. Alpha-lipoic acid inhibits endotoxin-stimulated expression of iNOS and nitric oxide independent of the heat shock response in RAW 264.7 cells. Free Radical Research 38: 675–682.

    Article  CAS  PubMed  Google Scholar 

  3. Tyagi, N., and R. Tyagi. 2015. The wonderous chaperones: a highlight on therapeutics of cancer and potentially malignant disorders. Journal of Oral and Maxillofacial Pathology 19: 212–220.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Wieten, L., F. Broere, R. van der Zee, E.K. Koerkamp, J. Wagenaar, and W. van Eden. 2007. Cell stress induced HSP are targets of regulatory T cells: a role for HSP inducing compounds as anti-inflammatory immuno-modulators? FEBS Letters 581: 3716–3722.

    Article  CAS  PubMed  Google Scholar 

  5. Kim, I., H.M. Shin, and W. Baek. 2005. Heat-shock response is associated with decreased production of interleukin-6 in murine aortic vascular smooth muscle cells. Naunyn-Schmiedeberg's Archives of Pharmacology 371: 27–33.

    Article  CAS  PubMed  Google Scholar 

  6. Pockley, A.G., S.K. Calderwood, and G. Multhoff. 2009. The atheroprotective properties of Hsp70: a role for Hsp70-endothelial interactions? Cell Stress & Chaperones 14: 545–553.

    Article  CAS  Google Scholar 

  7. Bast, A., and G.R. Haenen. 1988. Interplay between lipoic acid and glutathione in the protection against microsomal lipid peroxidation. Biochimica et Biophysica Acta 963: 558–561.

    Article  CAS  PubMed  Google Scholar 

  8. Maczurek, A., K. Hager, M. Kenklies, M. Sharman, R. Martins, J. Enge, D.A. Carlson, and G. Münch. 2008. Lipoic acid as an anti-inflammatory and neuroprotective treatment for Alzheimer's disease. Advanced Drug Delivery Reviews 60: 1463–1470.

    Article  CAS  PubMed  Google Scholar 

  9. Petronilho, F., D. Florentino, L.G. Danielski, L.C. Vieira, M.M. Martins, A. Vieira, S. Bonfante, M.P. Goldim, and F. Vuolo. 2015. Alpha-Lipoic Acid Attenuates Oxidative Damage in Organs After Sepsis. Inflammation Oct 2.

  10. Gorąca, A., H. Huk-Kolega, A. Piechota, P. Kleniewska, E. Ciejka, and B. Skibska. 2011. Lipoic acid—biological activity and therapeutic potential. Pharmacological Reports 63: 849–858.

    Article  PubMed  Google Scholar 

  11. Gianturco, V., A. Bellomo, E. D'Ottavio, V. Formosa, A. Iori, M. Mancinella, G. Troisi, and V. Marigliano. 2009. Impact of therapy with alpha-lipoic acid (ALA) on the oxidative stress in the controlled NIDDM: a possible preventive way against the organ dysfunction? Archives of Gerontology and Geriatrics 49(Suppl 1): 129–133.

    Article  CAS  PubMed  Google Scholar 

  12. Kiemer, A.K., C. Müller, and A.M. Vollmar. 2002. Inhibition of LPS-induced nitric oxide and TNF-alpha production by alpha-lipoic acid in rat Kupffer cells and in RAW 264.7 murine macrophages. Immunology and Cell Biology 80: 550–557.

    Article  CAS  PubMed  Google Scholar 

  13. Zhang, W.J., and B. Frei. 2001. Alpha-lipoic acid inhibits TNF-alpha-induced NF-kappaB activation and adhesion molecule expression in human aortic endothelial cells. The FASEB Journal 15: 2423–2432.

    Article  CAS  PubMed  Google Scholar 

  14. Wong, A., S. Dukic-Stefanovic, J. Gasic-Milenkovic, R. Schinzel, H. Wiesinger, P. Riederer, and G. Münch. 2001. Anti-inflammatory antioxidants attenuate the expression of inducible nitric oxide synthase mediated by advanced glycation endproducts in murine microglia. European Journal of Neuroscience 14: 1961–1967.

    Article  CAS  PubMed  Google Scholar 

  15. Bierhaus, A., S. Chevion, M. Chevion, M. Hofmann, P. Quehenberger, T. Illmer, T. Luther, E. Berentshtein, H. Tritschler, M. Müller, P. Wahl, R. Ziegler, and P.P. Nawroth. 1997. Advanced glycation end product-induced activation of NF-kappaB is suppressed by alpha-lipoic acid in cultured endothelial cells. Diabetes 46: 1481–1490.

    Article  CAS  PubMed  Google Scholar 

  16. Wollin, S.D., and P.J.H. Jones. 2003. α-lipoic acid and cardiovascular disease. Journal of Nutrition 133: 3327–3330.

    CAS  PubMed  Google Scholar 

  17. Xiao, Z.Q., L. Moragoda, R. Jaszewski, J.A. Hatfield, S.E.G. Fligiel, and A.P.N. Majumdar. 2001. Aging is associated with increased proliferation and decreased apoptosis in the colonic mucosa. Mechanisms of Ageing and Development 122: 1849–1864.

    Article  CAS  PubMed  Google Scholar 

  18. Bertolotto, F., and A. Massone. 2012. Combination of alpha lipoic acid and superoxide dismutase leads to physiological and symptomatic improvements in diabetic neuropathy. Drugs in R&D 12: 29–34.

    Article  CAS  Google Scholar 

  19. Hirano, T. 1998. Interleukin 6 and its receptor: ten years later. International Reviews of Immunology 16: 249–284.

    Article  CAS  PubMed  Google Scholar 

  20. Conti, B., I. Tabarean, C. Andrei, and T. Bartfai. 2004. Cytokines and fever. Frontiers in Bioscience 9: 1433–1449.

    Article  CAS  PubMed  Google Scholar 

  21. Nagaraju, K., N. Raben, G. Merritt, L. Loeffler, K. Kirk, and P. Plotz. 1998. A variety of cytokines and immunologically relevant surface molecules are expressed by normal human skeletal muscle cells under proinflammatory stimuli. Clinical and Experimental Immunology 113: 407–414.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ostrowski, K., T. Rohde, M. Zacho, S. Asp, and B.K. Pedersen. 1998. Evidence that interleukin-6 is produced in human skeletal muscle during prolonged running. The Journal of Physiology 508: 949–953.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kosmidou, I., T. Vassilakopoulos, A. Xagorari, S. Zakynthinos, A. Papapetropoulos, and C. Roussos. 2002. Production of interleukin-6 by skeletal myotubes: role of reactive oxygen species. American Journal of Respiratory Cell and Molecular Biology 26: 587–593.

    Article  CAS  PubMed  Google Scholar 

  24. Welc, S.S., N.A. Phillips, J. Oca-Cossio, S.M. Wallet, D.L. Chen, and T.L. Clanton. 2012. Hyperthermia increases interleukin-6 in mouse skeletal muscle. American Journal of Physiology - Cell Physiology 303: C455–466.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Welc, S.S., A.R. Judge, and T.L. Clanton. 2013. Skeletal muscle interleukin-6 regulation in hyperthermia. American Journal of Physiology - Cell Physiology 305: C406–413.

    Article  CAS  PubMed  Google Scholar 

  26. Pedersen, B.K., and M.A. Febbraio. 2008. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiological Reviews 88: 1379–1406.

    Article  CAS  PubMed  Google Scholar 

  27. Portier, G.L., A.G. Benders, A. Oosterhof, J.H. Veerkamp, and T.H. van Kuppevelt. 1999. Differentiation markers of mouse C2C12 and rat L6 myogenic cell lines and the effect of the differentiation medium. In Vitro Cellular and Developmental Biology Animal 35: 219–227.

    Article  CAS  PubMed  Google Scholar 

  28. Wu, P.F., S.C. Luo, and L.C. Chang. 2015. Heat-shock-induced glucose transporter 4 in the slow-twitch muscle of rats. Physiological Research 64: 523–530.

    PubMed  Google Scholar 

  29. Fridovich, I. 1995. Superoxide radical and superoxide dismutases. Annual Review of Biochemistry 64: 97–112.

    Article  CAS  PubMed  Google Scholar 

  30. Kirkman, H.N., and G.F. Gaetani. 2007. Mammalian catalase: a venerable enzyme with new mysteries. Trends in Biochemical Sciences 32: 44–50.

    Article  CAS  PubMed  Google Scholar 

  31. Chada, S., C. Whitney, and P.E. Newburger. 1989. Post-transcriptional regulation of glutathione peroxidase gene expression by selenium in the HL-60 human myeloid cell line. Blood 74: 2535–2541.

    CAS  PubMed  Google Scholar 

  32. Mihara, M., M. Hashizume, H. Yoshida, M. Suzuki, and M. Shiina. 2012. IL-6/IL-6 receptor system and its role in physiological and pathological conditions. Clinical Science (London, England : 1979) 122: 143–159.

    Article  CAS  Google Scholar 

  33. Rose-John, S. 2012. IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6. International Journal of Biological Sciences 8: 1237–1247.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Muñoz-Cánoves, P., C. Scheele, B.K. Pedersen, and A.L. Serrano. 2013. Interleukin-6 myokine signaling in skeletal muscle: a double-edged sword? FEBS Journal 280: 4131–4148.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Kostek, M.C., K. Nagaraju, E. Pistilli, A. Sali, S.H. Lai, B. Gordon, and Y.W. Chen. 2012. IL-6 signaling blockade increases inflammation but does not affect muscle function in the mdx mouse. BMC Musculoskeletal Disorders 13: 106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Starkie, R., S.R. Ostrowski, S. Jauffred, M. Febbraio, and B.K. Pedersen. 2003. Exercise and IL-6 infusion inhibit endotoxin-induced TNF-alpha production in humans. The FASEB Journal 17: 884–886.

    CAS  PubMed  Google Scholar 

  37. Jones, S.A., J. Scheller, and S. Rose-John. 2011. Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling. The Journal of Clinical Investigation 121: 3375–3383.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kishimoto, T. 2010. IL-6: from its discovery to clinical applications. International Immunology 22: 347–352.

    Article  CAS  PubMed  Google Scholar 

  39. Burton, M.D., N.L. Sparkman, and R.W. Johnson. 2011. Inhibition of interleukin-6 trans-signaling in the brain facilitates recovery from lipopolysaccharide-induced sickness behavior. Journal of Neuroinflammation 8: 54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Campbell, I.L., M. Erta, S.L. Lim, R. Frausto, U. May, S. Rose-John, J. Scheller, and J. Hidalgo. 2014. Trans-signaling is a dominant mechanism for the pathogenic actions of interleukin-6 in the brain. The Journal of Neuroscience 34: 2503–2513.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Pei-Fung Wu.

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This study was funded by a grant from Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan (ZBH104-14).

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The authors declare that they have no conflicts of interest.

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Lee, CT., Chang, LC. & Wu, PF. Lipoic Acid Exerts Antioxidant and Anti-inflammatory Effects in Response to Heat Shock in C2C12 Myotubes. Inflammation 39, 1160–1168 (2016). https://doi.org/10.1007/s10753-016-0350-2

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