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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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The expression analysis of mouse interleukin-6 splice variants argued against their biological relevance

  • Annibalini, Giosue (Dipartimento di Scienze Biomolecolari, Universita degli Studi di Urbino "Carlo Bo") ;
  • Guescini, Michele (Dipartimento di Scienze Biomolecolari, Universita degli Studi di Urbino "Carlo Bo") ;
  • Agostini, Deborah (Dipartimento di Scienze Biomolecolari, Universita degli Studi di Urbino "Carlo Bo") ;
  • De Matteis, Rita (Dipartimento di Scienze Biomolecolari, Universita degli Studi di Urbino "Carlo Bo") ;
  • Sestili, Piero (Dipartimento di Scienze Biomolecolari, Universita degli Studi di Urbino "Carlo Bo") ;
  • Tibollo, Pasquale (Dipartimento di Scienze Biomolecolari, Universita degli Studi di Urbino "Carlo Bo") ;
  • Mantuano, Michela (Dipartimento di Scienze Biomolecolari, Universita degli Studi di Urbino "Carlo Bo") ;
  • Martinelli, Chiara (Dipartimento di Scienze Biomolecolari, Universita degli Studi di Urbino "Carlo Bo") ;
  • Stocchi, Vilberto (Dipartimento di Scienze Biomolecolari, Universita degli Studi di Urbino "Carlo Bo")
  • Received : 2011.08.16
  • Accepted : 2011.10.11
  • Published : 2012.01.31
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Abstract

Alternative splicing generates several interleukin-6 (IL-6) isoforms; for them an antagonistic activity to the wild-type IL-6 has been proposed. In this study we quantified the relative abundance of IL-6 mRNA isoforms in a panel of mouse tissues and in C2C12 cells during myoblast differentiation or after treatment with the $Ca^{2+}$ ionophore A23187, the AMP-mimetic AICAR and TNF-${\alpha}$. The two mouse IL-6 isoforms identified, IL-6${\delta}$5 (deletion of the first 58 bp of exon 5) and IL-6${\delta}$3 (lacking exon 3), were not conserved in rat and human, did not exhibit tissue specific regulation, were expressed at low levels and their abundance closely correlated to that of full-length IL-6. Species-specific features of the IL-6 sequence, such as the presence of competitive 3' acceptor site in exon 5 and insertion of retrotransposable elements in intron 3, could explain the production of IL-6${\delta}$5 and IL-6${\delta}$3. Our results argued against biological significance for mouse IL-6 isoforms.

Keywords

References

  1. Hong, D. S., Angelo, L. S. and Kurzrock, R. (2007) Interleukin-6 and its receptor in cancer: implications for Translational Therapeutics. Cancer 110, 1911-1928. https://doi.org/10.1002/cncr.22999
  2. Simpson, R. J., Hammacher, A., Smith, D. K., Matthews, J. M. and Ward, L. D. (1997) Interleukin-6: structure-function relationships. Protein Sci. 6, 929-955. https://doi.org/10.1002/pro.5560060501
  3. Kestler, D. P., Agarwal, S., Cobb, J., Goldstein, K. M. and Hall, R. E. (1995) Detection and analysis of an alternatively spliced isoform of interleukin-6 mRNA in peripheral blood mononuclear cells. Blood 86, 4559-4567.
  4. Alberti, L., Bachelot, T., Duc, A., Biota, C. and Blay, J. Y. (2005) A spliced isoform of interleukin 6 mRNA produced by renal cell carcinoma encodes for an interleukin 6 inhibitor. Cancer Res. 65, 2-5.
  5. Bihl, M. P., Heinimann, K., Rudiger, J. J., Eickelberg, O., Perruchoud, A. P., Tamm, M. and Roth, M. (2002) Identification of a novel IL-6 isoform binding to the endogenous IL-6 receptor. Am. J. Respir. Cell. Mol. Biol. 27, 48-56. https://doi.org/10.1165/ajrcmb.27.1.4637
  6. Yatsenko, O. P., Filipenko, M. L., Khrapov, E. A., Voronina, E. N., Kozlov, V. A. and Sennikov, S. V. (2004) Alternative splicing of mRNA of mouse interleukin-4 and interleukin-6. Cytokine 28, 190-196. https://doi.org/10.1016/j.cyto.2004.08.009
  7. Denessiouk, K. A., Denesyuk, A. I. and Johnson, M. S. (2008) Negative modulation of signal transduction via interleukin splice variation. Proteins 71, 751-770. https://doi.org/10.1002/prot.21756
  8. Pedersen, B. K. and Fischer, C. P. (2007) Physiological roles of muscle-derived interleukin-6 in response to exercise. Curr. Opin. Clin. Nutr. Metab. Care. 10, 265-271. https://doi.org/10.1097/MCO.0b013e3280ebb5b3
  9. Baeza-Raja, B. and Munoz-Canoves, P. (2004) p38 MAPKinduced nuclear factor-kappaB activity is required for skeletal muscle differentiation: role of interleukin-6. Mol. Biol. Cell. 15, 2013-2026. https://doi.org/10.1091/mbc.E03-08-0585
  10. Al-Shanti, N., Saini, A., Faulkner, S. H. and Stewart, C. E. (2008) Beneficial synergistic interactions of TNF-alpha and IL-6 in C2 skeletal myoblasts--potential cross-talk with IGF system. Growth Factors 26, 61-73. https://doi.org/10.1080/08977190802025024
  11. Weigert, C., Dufer, M., Simon, P., Debre, E., Runge, H., Brodbeck, K., Haring, H. U. and Schleicher, E. D. (2007) Upregulation of IL-6 mRNA by IL-6 in skeletal muscle cells: role of IL-6 mRNA stabilization and Ca2+-dependent mechanisms. Am. J. Physiol. Cell. Physiol. 293, C1139-1147. https://doi.org/10.1152/ajpcell.00142.2007
  12. Glund, S., Treebak, J. T., Long, Y. C., Barres, R., Viollet, B., Wojtaszewski, J. F. and Zierath, J. R. (2009) Role of adenosine 5'-monophosphate-activated protein kinase in intreleukin- 6 release from isolated mouse skeletal muscle. Endocrinology 150, 600-606. https://doi.org/10.1210/en.2008-1204
  13. Dreyfuss, G., Kim, V. N. and Kataoka, N. (2002) Messenger- RNA-binding proteins and the messages they carry. Nat. Rev. Mol. Cell. Biol. 3, 195-205. https://doi.org/10.1038/nrm760
  14. Serrano, A. L., Baeza-Raja, B., Perdiguero, E., Jardi, M. and Munoz-Canoves, P. (2008) Interleukin-6 is an essential regulator of satellite cell-mediated skeletal muscle hypertrophy. Cell. Metab. 7, 33-44. https://doi.org/10.1016/j.cmet.2007.11.011
  15. Schwartz, S., Hall, E. and Ast, G. (2009) SROOGLE: webserver for integrative, user-friendly visualization of splicing signals. Nucleic Acids Res. 37, W189-192. https://doi.org/10.1093/nar/gkp320
  16. Xia, H., Bi, J. and Li, Y. (2006) Identification of alternative 5'/3' splice sites based on the mechanism of splice site competition. Nucleic Acids Res. 34, 6305-6313. https://doi.org/10.1093/nar/gkl900
  17. Meischl, C., Boer, M., Ahlin, A. and Roos, D. (2000) A new exon created by intronic insertion of a rearranged LINE-1 element as the cause of chronic granulomatous disease. Eur. J. Hum. Genet. 8, 697-703. https://doi.org/10.1038/sj.ejhg.5200523
  18. Han, J. S. and Boeke, J. D. (2005) LINE-1 retrotransposons: modulators of quantity and quality of mammalian gene expression? Bioessays 27, 775-784. https://doi.org/10.1002/bies.20257
  19. Fox-Walsh, K. L. and Hertel, K. J. (2009) Splice-site pairing is an intrinsically high fidelity process. Proc. Natl. Acad. Sci. U.S.A. 106, 1766-1771. https://doi.org/10.1073/pnas.0813128106
  20. Pan, Q., Shai, O., Lee, L. J., Frey, B. J. and Blencowe, B. J. (2008) Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing. Nat. Genet. 40, 1413-1415. https://doi.org/10.1038/ng.259
  21. Melamud, E. and Moult, J. (2009) Stochastic noise in splicing machinery. Nucleic Acids Res. 37, 4873-4886. https://doi.org/10.1093/nar/gkp471
  22. Hsu, S. N. and Hertel, K. J. (2009) Spliceosomes walk the line: splicing errors and their impact on cellular function. RNA Biol. 6, 526-530. https://doi.org/10.4161/rna.6.5.9860
  23. Sestili, P., Barbieri, E., Martinelli, C., Battistelli, M., Guescini, M., Vallorani, L., Casadei, L., D'Emilio, A., Falcieri, E., Piccoli, G., Agostini, D., Annibalini, G., Paolillo, M., Gioacchini, A. M. and Stocchi, V. (2009) Creatine supplementation prevents the inhibition of myogenic differentiation in oxidatively injured C2C12 murine myoblasts. Mol. Nutr. Food. Res. 53, 1187-1204. https://doi.org/10.1002/mnfr.200800504
  24. Overbergh, L., Valckx, D., Waer, M. and Mathieu, C. (1999) Quantification of murine cytokine mRNAs using real time quantitative reverse transcriptase PCR. Cytokine. 11, 305-312. https://doi.org/10.1006/cyto.1998.0426
  25. Wang, Y., Zhu, W. and Levy, D. E. (2006) Nuclear and cytoplasmic mRNA quantification by SYBR green based real- time RT-PCR. Methods 39, 356-362. https://doi.org/10.1016/j.ymeth.2006.06.010

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