Biochemistry (Moscow)

, Volume 82, Issue 11, pp 1276–1284 | Cite as

Antiinflammatory effect of rosiglitazone via modulation of mRNA stability of interleukin 10 and cyclooxygenase 2 in astrocytes

  • E. V. Pankevich
  • A. A. Astakhova
  • D. V. ChistyakovEmail author
  • M. G. Sergeeva


Investigation of molecular mechanisms of proinflammatory stimuli signaling in astrocytes is important for understanding their role in pathogenesis of central nervous system diseases as well as in functioning of the innate immunity system in non-immune cells. Here we show that lipopolysaccharide (LPS) stimulation of primary rat astrocytes led to conventional inflammatory response: increase in both proinflammatory (tumor necrosis factor, TNFα; prostaglandin E2, PGE2) and antiinflammatory marker (interleukin 10, IL-10) levels. The protein level of cyclooxygenase 2 (COX-2) was also increased. Rosiglitazone strengthened LPS-induced mRNA expression of COX-2 and IL-10 but not TNFα. Rosiglitazone is an agonist of nuclear receptor PPARγ, but its impact on IL-10 expression was not influenced by a PPARγ antagonist, GW9662, suggesting PPARγ-independent effect of rosiglitazone. The degradation of mRNA is one of the steps of inflammation regulation and might be affected by small molecules. In experiments with actinomycin D, we found that mRNA half-lives of IL-10, COX-2, and TNFα in naive astrocytes were 70, 44, and 19 min, respectively. LPS stimulation caused 2-fold increase in IL-10 and COX-2 mRNA decay rates, whereas addition of rosiglitazone restored them to the initial level. TNFα decay rate was not changed by these stimulations. This suggests that mRNA decay rate could be regulated by small molecules. Moreover, rosiglitazone could be used as a substance stimulating the resolution of inflammation without influence on proinflammatory signals. These results open new perspectives in the search for inflammation resolution modulators.


rosiglitazone inflammatory response astrocytes mRNA stability 



central nervous system


cyclooxygenase 2


interleukin 10




prostaglandin E2


toll-like receptor 4


tumor necrosis factor alpha


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  1. 1.
    Amor, S., Peferoen, L. A., Vogel, D. Y., Breur, M., Van der Valk, P., Baker, D., and Van Noort, J. M. (2014) Inflammation in neurodegenerative diseases–an update, Immunology, 142, 151–166.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Carta, A. R. (2013) PPAR-γ: therapeutic prospects in Parkinson’s disease, Curr. Drug Targets, 14, 743–751.CrossRefPubMedGoogle Scholar
  3. 3.
    Heneka, M. T., and Landreth, G. E. (2007) PPARs in the brain, Biochim. Biophys. Acta, 1771, 1031–1045.CrossRefPubMedGoogle Scholar
  4. 4.
    Rainsford, K. D. (2007) Anti-inflammatory drugs in the 21st century, Subcell. Biochem., 42, 3–27.CrossRefPubMedGoogle Scholar
  5. 5.
    Rolland, B., Deguil, J., Jardri, R., Cottencin, O., Thomas, P., and Bordet, R. (2013) Therapeutic prospects of PPARs in psychiatric disorders: a comprehensive review, Curr. Drug. Targets, 14, 724–732.CrossRefPubMedGoogle Scholar
  6. 6.
    Stulc, T., Svobodova, H., Krupickova, Z., Dolezalova, R., Marinov, I., and Ceska, R. (2014) Rosiglitazone influences the expression of leukocyte adhesion molecules and CD14 receptor in type 2 diabetes mellitus patients, Physiol. Res., 63 (Suppl. 2), S293–298.PubMedGoogle Scholar
  7. 7.
    Landreth, G., Jiang, Q., Mandrekar, S., and Heneka, M. (2008) PPARγ agonists as therapeutics for the treatment of Alzheimer’s disease, Neurotherapeutics, 5, 481–489.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Croasdell, A., Duffney, P. F., Kim, N., Lacy, S. H., Sime, P. J., and Phipps, R. P. (2015) PPARγ and the innate immune system mediate the resolution of inflammation, PPAR Res., 2015, 549691.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Pisanu, A., Lecca, D., Mulas, G., Wardas, J., Simbula, G., Spiga, S., and Carta, A. R. (2014) Dynamic changes in pro-and anti-inflammatory cytokines in microglia after PPAR-γ agonist neuroprotective treatment in the MPTPp mouse model of progressive Parkinson’s disease, Neurobiol. Dis., 71, 280–291.CrossRefPubMedGoogle Scholar
  10. 10.
    Li, X., Xu, B., Wang, Y., and Wei, L. (2014) Anti-inflam-matory effect of peroxisome proliferator-activated recep-tor-γ (PPAR-γ) on non-obese diabetic mice with Sjogren’s syndrome, Int. J. Clin. Exp. Pathol., 7, 4886–4894.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Chistyakov, D. V., Aleshin, S., Sergeeva, M. G., and Reiser, G. (2014) Regulation of peroxisome proliferator-activated receptor β/δ expression and activity levels by toll-like receptor agonists and MAP kinase inhibitors in rat astro-cytes, J. Neurochem., 130, 563–574.CrossRefPubMedGoogle Scholar
  12. 12.
    Astakhova, A. A., Chistyakov, D. V., Pankevich, E. V., and Sergeeva, M. G. (2015) Regulation of cyclooxygenase 2 expression by agonists of PPAR nuclear receptors in the model of endotoxin tolerance in astrocytes, Biochemistry (Moscow), 80, 1262–1270.CrossRefGoogle Scholar
  13. 13.
    Chistyakov, D. V., Aleshin, S. E., Astakhova, A. A., Sergeeva, M. G., and Reiser, G. (2015) Regulation of per-oxisome proliferator-activated receptors (PPAR) α and -γ of rat brain astrocytes in the course of activation by toll-like receptor agonists, J. Neurochem., 134, 113–124.CrossRefPubMedGoogle Scholar
  14. 14.
    Anderson, P. (2010) Post-transcriptional regulons coordi-nate the initiation and resolution of inflammation, Nat. Rev. Immunol., 10, 24–35.CrossRefPubMedGoogle Scholar
  15. 15.
    Basil, M. C., and Levy, B. D. (2016) Specialized pro-resolving mediators: endogenous regulators of infection and inflammation, Nat. Rev. Immunol., 16, 51–67.CrossRefPubMedGoogle Scholar
  16. 16.
    Livak, K. J., and Schmittgen, T. D. (2001) Analysis of rela-tive gene expression data using real-time quantitative PCR and the 2(–ΔΔC(T)) method, Methods, 25, 402–408.CrossRefPubMedGoogle Scholar
  17. 17.
    Ross, J. (1995) mRNA stability in mammalian cells, Microbiol. Rev., 59, 423–450.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Chen, C. A., Ezzeddine, N., and Shyu, A. (2008) Chapter 17. Messenger RNA half-life measurements in mam-malian cells, in RNA Turnover in Eukaryotes: Nucleases, Pathways and Analysis of mRNA Decay, Elsevier, pp. 335–357.CrossRefGoogle Scholar
  19. 19.
    Aleshin, S., Grabeklis, S., Hanck, T., Sergeeva, M., and Reiser, G. (2009) Peroxisome proliferator-activated recep-tor (PPAR)-γ positively controls and PPARα negatively controls cyclooxygenase-2 expression in rat brain astrocytes through a convergence on PPARβ/δ via mutual control of PPAR expression levels, Mol. Pharmacol., 76, 414–424.CrossRefPubMedGoogle Scholar
  20. 20.
    Park, E. J., Park, S. Y., Joe, E.-H., and Jou, I. (2003) 15 d-PGJ2 and rosiglitazone suppress Janus kinase-STAT inflammatory signaling through induction of suppressor of cytokine signaling 1 (SOCS1) and SOCS3 in glia, J. Biol. Chem., 278, 14747–14752.CrossRefPubMedGoogle Scholar
  21. 21.
    Luna-Medina, R., Cortes-Canteli, M., Alonso, M., Santos, A., Martinez, A., and Perez-Castillo, A. (2005) Regulation of inflammatory response in neural cells in vitro by thiadiazolidinones derivatives through peroxisome pro-liferator-activated receptor γ activation, J. Biol. Chem., 280, 21453–21462.CrossRefPubMedGoogle Scholar
  22. 22.
    Schiefelbein, D., Seitz, O., Goren, I., Dissmann, J. P., Schmidt, H., Bachmann, M., Sader, R., Geisslinger, G., Pfeilschifter, J., and Frank, S. (2008) Keratinocyte-derived vascular endothelial growth factor biosynthesis represents a pleiotropic side effect of peroxisome proliferator-activated receptor-agonist troglitazone but not rosiglitazone and involves activation of p38 mitogen-activated protein kinase: implications for diabetes-impaired skin repair, Mol. Pharmacol., 74, 952–963.CrossRefPubMedGoogle Scholar
  23. 23.
    Pankevich, E. V., Chistyakov, D. V., Astakhova, A. A., Strelkova, O. S., and Sergeeva, M. G. (2015) Regulation of cyclooxygenase 2 mRNA degradation by rosiglitazone in C6 glioma cells in the presence of inflam-mation inductors, Biol. Membr., 9, 337–341.Google Scholar
  24. 24.
    Takeda, K., and Akira, S. (2005) Toll-like receptors in innate immunity, Int. Immunol., 17, 1–14.CrossRefPubMedGoogle Scholar
  25. 25.
    Heales, S. J. R., Lam, A. A. J., Duncan, A. J., and Land, J. M. (2004) Neurodegeneration or neuroprotection: the piv-otal role of astrocytes, Neurochem. Res., 29, 513–519.CrossRefPubMedGoogle Scholar
  26. 26.
    Font-Nieves, M., Sans-Fons, M. G., Gorina, R., Bonfill-Teixidor, E., Salas-Perdomo, A., Marquez-Kisinousky, L., Santalucia, T., and Planas, A. M. (2012) Induction of COX-2 enzyme and down-regulation of COX-1 expression by lipopolysaccharide (LPS) control prostaglandin E2 pro-duction in astrocytes, J. Biol. Chem., 287, 6454–6468.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Sergeeva, M. G., and Varfolomeeva, A. T. (2006) The Cascade of Arachidonic Acid [in Russian], Narodnoe Obrazovanie, Moscow.Google Scholar
  28. 28.
    Ortega-Gomez, A., Perretti, M., and Soehnlein, O. (2013) Resolution of inflammation: an integrated view, EMBO Mol. Med., 5, 661–674.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Sugimoto, M. A., Sousa, L. P., Pinho, V., Perretti, M., and Teixeira, M. M. (2016) Resolution of inflammation: what controls its onset? Front. Immunol., 7, 160.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Serhan, C. N., Chiang, N., Dalli, J., and Levy, B. D. (2014) Lipid mediators in the resolution of inflammation, Cold Spring Harb. Perspect. Biol., 7, a016311.Google Scholar
  31. 31.
    MacKenzie, K. F., Van Den Bosch, M. W. M., Naqvi, S., Elcombea, S. E., McGuirea, V. A., Reithb, A. D., Blackshearc, P. J., Deand, J. L. E., and Arthura, J. S. C. (2013) MSK1 and MSK2 inhibit lipopolysaccharide-induced prostaglandin production via an interleukin-10 feedback loop, Mol. Cell. Biol., 33, 1456–1467.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Bollmann, F., Wu, Z., Oelze, M., Siuda, D., Xia, N., Henke, J., Daiber, A., Li, H., Stumpo, D. J., Blackshear, P. J., Kleinert, H., and Pautz, A. (2014) Endothelial dysfunction in tristetraprolin-deficient mice is not caused by enhanced tumor necrosis factor-α expression, J. Biol. Chem., 289, 15653–15665.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Li, H., Pan, G.-F., Jiang, Z.-Z., Yang, J., Sun, L.-X., and Zhang, L.-Y. (2015) Triptolide inhibits human breast cancer MCF-7 cell growth via downregulation of the ERα-mediat-ed signaling pathway, Acta Pharmacol. Sin., 36, 606–613.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Subbaram, S., Lyons, S. P., Svenson, K. B., Hammond, S. L., McCabe, L. G., Chittur, S. V., and DiPersio, C. M. (2014) Integrin α3β1 controls mRNA splicing that deter-mines Cox-2 mRNA stability in breast cancer cells, J. Cell. Sci., 127, 1179–1189.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2017

Authors and Affiliations

  • E. V. Pankevich
    • 1
  • A. A. Astakhova
    • 2
  • D. V. Chistyakov
    • 2
    • 3
    Email author
  • M. G. Sergeeva
    • 2
  1. 1.Lomonosov Moscow State UniversityFaculty of Bioengineering and BioinformaticsMoscowRussia
  2. 2.Belozersky Institute of Physico-Chemical BiologyLomonosov Moscow State UniversityMoscowRussia
  3. 3.Pirogov Russian National Research Medical UniversityMoscowRussia

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