Biomolecules & Therapeutics

  • 제20권1호
  • /
  • Pages.43-49
  • /
  • 2012
  • /
  • 1976-9148(pISSN)
  • /
  • 2005-4483(eISSN)
한국응용약물학회 (The Korean Society of Applied Pharmacology)
권호 표지
DOI QR코드

DOI QR Code

Destabilization of TNF-α mRNA by Rapamycin

  • Park, Jong-Woo (Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University) ;
  • Jeon, Ye-Ji (Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University) ;
  • Lee, Jae-Cheol (Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University) ;
  • Ahn, So-Ra (Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University) ;
  • Ha, Shin-Won (Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University) ;
  • Bang, So-Young (Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University) ;
  • Park, Eun-Kyung (Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University) ;
  • Yi, Sang-Ah (Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University) ;
  • Lee, Min-Gyu (Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University) ;
  • Han, Jeung-Whan (Research Center for Epigenome Regulation, School of Pharmacy, Sungkyunkwan University)
  • 투고 : 2011.08.22
  • 심사 : 2011.12.27
  • 발행 : 2012.01.31
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Stimulation of mast cells through the high affinity IgE receptor (Fc${\varepsilon}$RI) induces degranulation, lipid mediator release, and cytokine secretion leading to allergic reactions. Although various signaling pathways have been characterized to be involved in the Fc${\varepsilon}$RI-mediated responses, little is known about the precious mechanism for the expression of tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$) in mast cells. Here, we report that rapamycin, a specific inhibitor of mammalian target of rapamycin (mTOR), reduces the expression of TNF-${\alpha}$ in rat basophilic leukemia (RBL-2H3) cells. IgE or specific antigen stimulation of RBL-2H3 cells increases the expression of TNF-${\alpha}$ and activates various signaling molecules including S6K1, Akt and p38 MAPK. Rapamycin specifically inhibits antigeninduced TNF-${\alpha}$ mRNA level, while other kinase inhibitors have no effect on TNF-${\alpha}$ mRNA level. These data indicate that mTOR signaling pathway is the main regulation mechanism for antigen-induced TNF-${\alpha}$ expression. TNF-${\alpha}$ mRNA stability analysis using reporter construct containing TNF-${\alpha}$ adenylate/uridylate-rich elements (AREs) shows that rapamycin destabilizes TNF-${\alpha}$ mRNA via regulating the AU-rich element of TNF-${\alpha}$ mRNA. The antigen-induced activation of S6K1 is inhibited by specific kinase inhibitors including mTOR, PI3K, PKC and $Ca^{2+}$chelator inhibitor, while TNF-${\alpha}$ mRNA level is reduced only by rapamycin treatment. These data suggest that the effects of rapamycin on the expression of TNF-${\alpha}$ mRNA are not mediated by S6K1 but regulated by mTOR. Taken together, our results reveal that mTOR signaling pathway is a novel regulation mechanism for antigen-induced TNF-${\alpha}$ expression in RBL-2H3 cells.

키워드

참고문헌

  1. Bae, G. U., Kim, Y. K., Kwon, H. K., Park, J. W., Lee, E. K., Paek, S. J., Choi, W. S., Jung, I. D., Lee, H. Y., Cho, E. J., Lee, H. W. and Han, J. W. (2004) Hydrogen peroxide mediates Rac1 activation of S6K1. Exp. Cell Res. 300, 476-484. https://doi.org/10.1016/j.yexcr.2004.07.013
  2. Bae, G. U., Seo, D. W., Kwon, H. K., Lee, H. Y., Hong, S., Lee, Z. W., Ha, K. S., Lee, H. W. and Han, J. W. (1999) Hydrogen peroxide activates p70(S6k) signaling pathway. J. Biol. Chem. 274, 32596-32602. https://doi.org/10.1074/jbc.274.46.32596
  3. Bakheet, T., Frevel, M., Williams, B. R., Greer, W. and Khabar, K. S. (2001) ARED: human AU-rich element-containing mRNA database reveals an unexpectedly diverse functional repertoire of encoded proteins. Nucleic. Acids Res. 29, 246-254. https://doi.org/10.1093/nar/29.1.246
  4. Banholzer, R., Nair, A. P., Hirsch, H. H., Ming, X. F. and Moroni, C. (1997) Rapamycin destabilizes interleukin-3 mRNA in autocrine tumor cells by a mechanism requiring an intact 3' untranslated region. Mol. Cell Biol. 17, 3254-3260.
  5. Beaven, M. A. and Metzger, H. (1993) Signal transduction by Fc receptors: the Fc epsilon RI case. Immunol. Today 14, 222-226. https://doi.org/10.1016/0167-5699(93)90167-J
  6. Boyce, J. A. (2003) The role of mast cells in asthma. Prostaglandins Leukot. Essent. Fatty. Acids. 69, 195-205. https://doi.org/10.1016/S0952-3278(03)00081-4
  7. Brown, E. J., Albers, M. W., Shin, T. B., Ichikawa, K., Keith, C. T., Lane, W. S. and Schreiber, S. L. (1994) A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature. 369, 756-758. https://doi.org/10.1038/369756a0
  8. Chang, E. Y., Szallasi, Z., Acs, P., Raizada, V., Wolfe, P. C., Fewtrell, C., Blumberg, P. M. and Rivera, J. (1997) Functional effects of overexpression of protein kinase C-alpha, -beta, -delta, -epsilon, and -eta in the mast cell line RBL-2H3. J. Immunol. 159, 2624-2632.
  9. Ching, T. T., Hsu, A. L., Johnson, A. J. and Chen, C. S. (2011) Phosphoinositide 3-kinase facilitates antigen-stimulated $Ca^{2+}$ infl ux in RBL-2H3 mast cells via a phosphatidylinositol 3,4,5-trisphosphatesensitive $Ca^{2+}$ entry mechanism. J. Biol. Chem. 276, 14814-14820.
  10. Clark, A. (2000) Post-transcriptional regulation of pro-infl ammatory gene expression. Arthritis. Res. 2, 172-174. https://doi.org/10.1186/ar83
  11. Combates, N. J., Degiannis, D., Raskova, J. and Raska, K. Jr. (1995) Direct inhibition of human CD8+ lymphocyte activation by cyclosporine A and Rapamune-Sirolimus. Clin. Immunol. Immunopathol. 77, 221-228. https://doi.org/10.1006/clin.1995.1147
  12. Dann, S. G., Selvaraj, A. and Thomas, G. (2007) mTOR Complex1-S6K1 signaling: at the crossroads of obesity, diabetes and cancer. Trends Mol. Med. 13, 252-259. https://doi.org/10.1016/j.molmed.2007.04.002
  13. Eiseman, E. and Bolen, J. B. (1992) Engagement of the high-affi nity IgE receptor activates src protein-related tyrosine kinases. Nature. 355, 78-80. https://doi.org/10.1038/355078a0
  14. Galli, S. J. (1993) New concepts about the mast cell. N. Engl. J. Med. 328, 257-265. https://doi.org/10.1056/NEJM199301283280408
  15. Garneau, N. L., Wilusz, J. and Wilusz, C. J. (2007) The highways and byways of mRNA decay. Nat. Rev. Mol. Cell Biol. 8, 113-126. https://doi.org/10.1038/nrm2104
  16. Gu, H., Saito, K., Klaman, L. D., Shen, J., Fleming, T., Wang, Y., Pratt, J. C., Lin, G., Lim, B., Kinet, J. P. and Neel, B. G. (2001) Essential role for Gab2 in the allergic response. Nature. 412, 186-190. https://doi.org/10.1038/35084076
  17. Hutchcroft, J. E., Geahlen, R. L., Deanin, G. G. and Oliver, J. M. (1992) Fc epsilon RI-mediated tyrosine phosphorylation and activation of the 72-kDa protein-tyrosine kinase, PTK72, in RBL-2H3 rat tumor mast cells. Proc. Natl. Acad. Sci. USA. 89, 9107-9111. https://doi.org/10.1073/pnas.89.19.9107
  18. Jabril-Cuenod, B., Zhang, C., Scharenberg, A. M., Paolini, R., Numerof, R., Beaven, M. A. and Kinet, J. P. (1996) Syk-dependent phosphorylation of Shc. A potential link between FcepsilonRI and the Ras/mitogen-activated protein kinase signaling pathway through SOS and Grb2. J. Biol. Chem. 271, 16268-16272. https://doi.org/10.1074/jbc.271.27.16268
  19. Jefferies, H. B., Fumagalli, S., Dennis, P. B., Reinhard, C., Pearson, R. B. and Thomas, G. (1997) Rapamycin suppresses 5'TOP mRNA translation through inhibition of p70s6k. EMBO J. 16, 3693-3704. https://doi.org/10.1093/emboj/16.12.3693
  20. Jung, D. K., Bae, G. U., Kim, Y. K., Han, S. H., Choi, W. S., Kang, H., Seo, D. W., Lee, H. Y., Cho, E. J., Lee, H. W. and Han, J. W. (2003) Hydrogen peroxide mediates arsenite activation of $p70^{s6k}$ and extracellular signal-regulated kinase. Exp. Cell Res. 290, 144-154. https://doi.org/10.1016/S0014-4827(03)00320-3
  21. Kawakami, Y., Yao, L., Miura, T., Tsukada, S., Witte, O. N. and Kawakami, T. (1994) Tyrosine phosphorylation and activation of Bruton tyrosine kinase upon Fc epsilon RI cross-linking. Mol. Cell Biol. 14, 5108-5113.
  22. Kontoyiannis, D., Pasparakis, M., Pizarro, T. T., Cominelli, F. and Kollias, G. (1999) Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gutassociated immunopathologies. Immunity. 10, 387-398. https://doi.org/10.1016/S1074-7613(00)80038-2
  23. Kopec, A., Panaszek, B. and Fal, A. M. (2006) Intracellular signaling pathways in IgE-dependent mast cell activation. Arch. Immunol. Ther. Exp. (Warsz). 54, 393-401. https://doi.org/10.1007/s00005-006-0049-4
  24. Kuo, C. J., Chung, J., Fiorentino, D. F., Flanagan, W. M., Blenis, J. and Crabtree, G. R. (1992) Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase. Nature. 358, 70-73. https://doi.org/10.1038/358070a0
  25. Lee, J. H., Chang, S. H., Park, Y. S., Her, E. , Lee, H. Y., Park, J. W., Han, J. W., Kim, Y. M. and Choi, W. S. (2004) In-vitro and in-vivo anti-allergic actions of Arecae semen. J. Pharm. Pharmacol. 56, 927-933. https://doi.org/10.1211/0022357023808
  26. Lee, R. J. and Oliver, J. M. (1995) Roles for $Ca^{2+}$ stores release and two $Ca^{2+}$ infl ux pathways in the Fc epsilon R1-activated $Ca^{2+}$ responses of RBL-2H3 mast cells. Mol. Biol Cell. 6, 825-839. https://doi.org/10.1091/mbc.6.7.825
  27. Li, W., Deanin, G. G., Margolis, B., Schlessinger, J. and Oliver, J. M. (1992) Fc epsilon R1-mediated tyrosine phosphorylation of multiple proteins, including phospholipase C gamma 1 and the receptor beta gamma 2 complex, in RBL-2H3 rat basophilic leukemia cells. Mol. Cell Biol. 12, 3176-3182.
  28. Millard, P. J., Gross, D., Webb, W. W. and Fewtrell, C. (1988) Imaging asynchronous changes in intracellular $Ca^{2+}$ in individual stimulated tumor mast cells. Proc. Natl. Acad. Sci. USA. 85, 1854-1858. https://doi.org/10.1073/pnas.85.6.1854
  29. Nakamura, T., Fonteh, A. N., Hubbard, W. C., Triggiani, M., Inagaki, N., Ishizaka, T. and Chilton, F. H. (1991) Arachidonic acid metabolism during antigen and ionophore activation of the mouse bone marrow derived mast cell. Biochim. Biophys Acta. 1085, 191-200. https://doi.org/10.1016/0005-2760(91)90094-X
  30. Pallet, N., Thervet, E., Le Corre, D., Knebelmann, B., Nusbaum, P., Tomkiewicz, C., Meria, P., Flinois, J. P., Beaune, P., Legendre, C. and Anglicheau, D. (2005) Rapamycin inhibits human renal epithelial cell proliferation: effect on cyclin D3 mRNA expression and stability. Kidney Int. 67, 2422-2433. https://doi.org/10.1111/j.1523-1755.2005.00350.x
  31. Ravetch, J. V. and Kinet, J. P. (1991) Fc receptors. Annu. Rev. Immunol. 9, 457-492. https://doi.org/10.1146/annurev.iy.09.040191.002325
  32. Razin, E., Pecht, I. and Rivera, J. (1995) Signal transduction in the activation of mast cells and basophils. Immunol. Today 16, 370-373. https://doi.org/10.1016/0167-5699(95)80003-4
  33. Shyu, A. B., Belasco, J. G. and Greenberg, M. E. (1991) Two distinct destabilizing elements in the c-fos message trigger deadenylation as a fi rst step in rapid mRNA decay. Genes Dev. 5, 221-231. https://doi.org/10.1101/gad.5.2.221
  34. Turner, H., Reif K,, Rivera, J. and Cantrell, D. A. (1995) Regulation of the adapter molecule Grb2 by the Fc epsilon R1 in the mast cell line RBL2H3. J. Biol. Chem. 270, 9500-9506. https://doi.org/10.1074/jbc.270.16.9500
  35. Um, S. H., D'Alessio, D. and Thomas, G. (2006) Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. Cell Metab. 3, 393-402. https://doi.org/10.1016/j.cmet.2006.05.003
  36. Weng, Q. P., Andrabi, K., Klippel, A., Kozlowski, M. T., Williams, L. T. and Avruch, J. (1995) Phosphatidylinositol 3-kinase signals activation of p70 S6 kinase in situ through site-specific p70 phosphorylation. Proc. Natl. Acad. Sci. USA. 92, 5744-5748. https://doi.org/10.1073/pnas.92.12.5744
  37. Wilson, B. S., Deanin, G. G., Standefer, J. C., Vanderjagt, D. and Oliver, J. M. (1989) Depletion of guanine nucleotides with mycophenolic acid suppresses IgE receptor-mediated degranulation in rat basophilic leukemia cells. J. Immunol. 143, 259-265.
  38. Xu, N., Chen, C. Y. and Shyu, A. B. (1997) Modulation of the fate of cytoplasmic mRNA by AU-rich elements: key sequence features controlling mRNA deadenylation and decay. Mol. Cell Biol. 17, 4611-4621.

피인용 문헌

  1. Vesicular Trafficking and Signaling for Cytokine and Chemokine Secretion in Mast Cells vol.5, 2014, https://doi.org/10.3389/fimmu.2014.00453
  2. Methoxyluteolin Inhibits Neuropeptide-stimulated Proinflammatory Mediator Release via mTOR Activation from Human Mast Cells vol.361, pp.3, 2012, https://doi.org/10.1124/jpet.117.240564
  3. A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: Immunological, physical performance, and cognitive effects vol.105, pp.None, 2012, https://doi.org/10.1016/j.exger.2017.12.026
  4. Mammalian Target of Rapamycin (mTOR) and the Proteasome Attenuates IL-1β Expression in Primary Mouse Cardiac Fibroblasts vol.10, pp.None, 2012, https://doi.org/10.3389/fimmu.2019.01285