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Activation of type-2 cannabinoid receptor inhibits neuroprotective and antiinflammatory actions of glucocorticoid receptor α: when one is better than two

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Abstract

Endocannabinoids (eCBs) and glucocorticoids (GCs) are two distinct classes of signaling lipids that exert both neuroprotective and immunosuppressive effects; however, the possibility of an actual interaction of their receptors [i.e., type-2 cannabinoid (CB2) and glucocorticoid receptor α (GRα), respectively] remains unexplored. Here, we demonstrate that the concomitant activation of CB2 and GRα abolishes the neuroprotective effects induced by each receptor on central neurons and on glial cells in animal models of remote cell death. We also show that the ability of eCBs and GCs, used individually, to inhibit tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) production from activated human T lymphocytes is lost when CB2 and GRα are activated simultaneously. In addition, signal transduction pathways triggered by concomitant activation of both receptors led to increased levels of GRβ, heat-shock proteins-70 and -90, and p-JNK, as well as to reduced levels of p-STAT6. These effects were reversed only by selectively antagonizing CB2, but not GRα. Overall, our study demonstrates for the first time the existence of a CB2-driven negative cross-talk between eCB and GC signaling in both rats and humans, thus paving the way to the possible therapeutic exploitation of CB2 as a new target for chronic inflammatory and neurodegenerative diseases.

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Acknowledgments

This study was supported by Wings for Life Spinal Cord Research Foundation to M.T. Viscomi, by the Ministero della Salute to M. Molinari, and partly by Fondazione TERCAS (grant 2009–2012) to M. Maccarrone.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Biomedical Sciences, University of Teramo, Piazza A. Moro 45, 64100, Teramo, Italy

    Elisa Bisicchia & Valerio Chiurchiù

  2. I.R.C.C.S. Santa Lucia Foundation, Via del Fosso di Fiorano 64, 00143, Rome, Italy

    Elisa Bisicchia, Valerio Chiurchiù, Maria Teresa Viscomi, Laura Latini, Filomena Fezza, Luca Battistini, Mauro Maccarrone & Marco Molinari

  3. Department of Experimental Medicine and Surgery, University of Rome “Tor Vergata”, Via Montpellier 1, 00133, Rome, Italy

    Filomena Fezza

  4. Fondazione S. Lucia, Via Ardeatina 306, 00179, Rome, Italy

    Marco Molinari

  5. Center of Integrated Research, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, 00128, Rome, Italy

    Mauro Maccarrone

Authors
  1. Elisa Bisicchia
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  2. Valerio Chiurchiù
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  3. Maria Teresa Viscomi
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  4. Laura Latini
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  5. Filomena Fezza
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  6. Luca Battistini
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  7. Mauro Maccarrone
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  8. Marco Molinari
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Corresponding author

Correspondence to Marco Molinari.

Additional information

E. Bisicchia and V. Chiurchiù contributed equally to the work.

M. Maccarrone and M. Molinari were equally senior authors.

Electronic supplementary material

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18_2012_1253_MOESM1_ESM.tif

Supplementary Fig. 1 Single or combined pharmacological activation of GRα and CB2 does not affect cytokine production from resting peripheral lymphocytes. Flow cytometric progressive gating and representative dot plots showing TNF-α and IFN-γ production from unstimulated CD4+ and CD8+ T lymphocytes treated or not with methylprednisolone (MPSS), JWH-015 or a combination of them (TIFF 28561 kb)

18_2012_1253_MOESM2_ESM.tif

Supplementary Fig. 2 Combined pharmacological activation of GRα and CB2 impairs cytokine production from peripheral lymphocytes. Histograms of TNF-α and IFN-γ production from unstimulated (CTRL) or PMA/Iono-activated CD4+ and CD8+ T lymphocytes treated or not with methylprednisolone (MPSS), GP 1A or a combination of them. One-way ANOVA (F = 10.06; p < 0.0001) followed by Bonferroni multiple comparison test was performed. Data are reported as mean ± SD (n=3). *p<0.01 versus PMA/Iono; # p<0.01 versus PMA/Iono-MPSS+GP 1A (TIFF 26571 kb)

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Bisicchia, E., Chiurchiù, V., Viscomi, M.T. et al. Activation of type-2 cannabinoid receptor inhibits neuroprotective and antiinflammatory actions of glucocorticoid receptor α: when one is better than two. Cell. Mol. Life Sci. 70, 2191–2204 (2013). https://doi.org/10.1007/s00018-012-1253-5

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