Abstract
An increased interest in neuroinflammation is conditioned by its involvement in various pathological processes in the brain. Astrocytes play an important role in neuroinflammation, participating in its regulation, throwing out a large number of signaling molecules. Steroid compounds, actively produced by astrocytes, are of interest with regards to the regulation of inflammatory processes in the central nervous system. In the present work the effect of dehydroepiandrosterone (DHEA) on astroglial cells (cultured primary rat astrocytes) in a model of inflammation was studied. The inflammatory response was stimulated with lipopolysaccharide (LPS). Expression levels of pro-inflammatory factor TNFα, antinflammatory interleukin IL-10, and both pro- and antiinflammatory protein COX-2 were measured. The expression of IL-10, COX-2, and TNFα mRNA was determined by real-time PCR, COX-2 protein level by immunoblotting method, TNFα and IL-10 release by enzyme immunoassay. The effect of short-term (30 min) and long-term (24 h) exposure to DHEA was evaluated. It was shown that DHEA potentiates LPS-stimulated (1) increase in the IL-10 mRNA level; (2) IL-10 release; (3) does not affect TNFα level, and (4) exerts a weak pulsating bidirectional effect on COX-2. Using trilostane, an inhibitor of 3β-hydroxysteroid dehydrogenase, a key enzyme of DHEA metabolism, it was shown that DHEA metabolites make the main contribution to its effect. Thus, DHEA is of interest as a stimulant of anti-inflammatory processes in the brain.
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Abbreviations
- CNS:
-
central nervous system
- COX-2:
-
cyclooxygenase 2
- LPS:
-
lipopolysaccharide
- TNFa:
-
tumor necrosis factor a
- IL-10:
-
interleukin 10
- DHEA:
-
dehydroepiandrosterone
References
DiSabato D.J., Quan N., Godbout J.P. 2016. Neuroinflammation: The devil is in the details. J. Neurochem. 139, 136–153.
Aleshin S., Strokin M., Sergeeva M., Reiser G. 2013. Peroxisome proliferator-activated receptor (PPAR)β/δ, a possible nexus of PPARα- and PPARγ-dependent molecular pathways in neurodegenerative diseases: Review and novel hypotheses. Neurochem. Int. 63, 322–330.
Lent R., Azevedo F.A.C., Andrade-Moraes C.H., Pinto A.V.O. 2012. How many neurons do you have? Some dogmas of quantitative neuroscience under revision. Eur. J. Neurosci. 35, 1–9.
Norden D.M., Fenn A.M., Dugan A., Godbout J.P. 2014. TGFβ produced by IL-10 redirected astrocytes attenuates microglial activation. Glia. 62, 881–895.
Choi Y.H., Park H.Y. 2012. Anti-inflammatory effects of spermidine in lipopolysaccharide-stimulated BV2 microglial cells. J. Biomed. Sci. 19, 31.
Laube G., Veh R.W. 1997. Astrocytes, not neurons, show most prominent staining for spermidine/spermine-like immunoreactivity in adult rat brain. Glia. 19, 171–179.
Olsen M.L., Khakh B.S., Skatchkov S.N., Zhou M., Lee C.J., Rouach N. 2015. New insights on astrocyte ion channels: Critical for homeostasis and neuron–glia signaling. J. Neurosci. 35, 13827–13835.
Skatchkov S.N., Woodbury-Fariña M.A., Eaton M. 2014. The role of glia in stress. Psychiatr. Clin. North Am. 37, 653–678.
Gresser O., Weber E., Hellwig A., Riese S., Régnier- Vigouroux A. 2001. Immunocompetent astrocytes and microglia display major differences in the processing of the invariant chain and in the expression of active cathepsin L and cathepsin S. Eur. J. Immunol. 31, 1813–1824.
Sofroniew M.V. 2015. Astrocyte barriers to neurotoxic inflammation. Nat. Rev. Neurosci. 16, 249–263.
Zwain I.H., Yen S.S. 1999. Dehydroepiandrosterone: Biosynthesis and metabolism in the brain. Endocrinology. 140, 880–887.
Arbo B.D., Bennetti F., Ribeiro M.F. 2016 Astrocytes as a target for neuroprotection: Modulation by progesterone and dehydroepiandrosterone. Prog. Neurobiol. 144, 27–47.
Goncharov N.P., Katsiya G.V., Nizhnik A.N. 2004. Formula zhizni. Degidroepiandrosteron: svoistva, metaboliizm, biologicheskoe znachenie (The formula of life. Dehydroepiandrosterone: Properties, metabolism, biological significance). M.: OOO Publishing Association Adamant.
Rutkowski K., Sowa P., Rutkowska-Talipska J., Kuryliszyn-Moskal A., Rutkowski R. 2014. Dehydroepiandrosterone (DHEA): Hypes and hopes. Drugs. 74, 1195–1207.
Chistyakov D.V., Aleshin S., Sergeeva M.G., 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 astrocytes. J. Neurochem. 130, 563–574.
Alexander C., Rietschel E.T. 2001. Bacterial lipopolysaccharides and innate immunity. J. Endotoxin Res. 7, 167–202.
Powell J.M., Sonnenfeld G. 2006. The effects of dehydroepiandrosterone (DHEA) on in vitro spleen cell proliferation and cytokine production. J. Interf. Cytokine Res. 26, 34–39.
Barkhausen T., Hildebrand F., Krettek C., van Griensven M. 2009. DHEA-dependent and organ-specific regulation of TNF-alpha mRNA expression in a murine polymicrobial sepsis and trauma model. Crit. Care. 13, R114.
Wu Z., Li L., Zheng L.-T., Xu Z., Guo L., Zhen X. 2015. Allosteric modulation of sigma-1 receptors by SKF83959 inhibits microglia-mediated inflammation. J. Neurochem. 134, 904–914.
Barger S.W., Chavis J.A., Drew P.D. 2000. Dehydroepiandrosterone inhibits microglial nitric oxide production in a stimulus-specific manner. J. Neurosci. Res. 62, 503–509.
Kuehn C.C., Oliveira L.G.R., Santos C.D., Augusto M.B., Toldo M.P.A., Do Prado J.C. 2011. Prior and concomitant dehydroepiandrosterone treatment affects immunologic response of cultured macrophages infected with Trypanosoma cruzi in vitro? Vet. Parasitol. 177, 242–246.
García-Estrada J., Luquín S., Fernández A.M., Garcia-segura L.M. 1999. Dehydroepiandrosterone, pregnenolone and sexsteroids down-regulate reactive astroglia in the male ratbrain after a penetrating brain injury. Int. J. Dev. Neurosci. 17, 145–151.
Astakhova A.A., Chistyakov D.V., Pankevich E.V., 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, 1532–1541.
Potts G.O., Creange J.E., Hardomg H.R., Schane H.P. 1978. Trilostane, an orally active inhibitor of steroid biosynthesis. Steroids. 32, 257–267.
Ledeboer A., Brevé J.J.P., Wierinckx A., van der Jagt S., Bristow A.F., Leysen J.E., Tilders F.J.H., Van Dam A.-M. 2002. Expression and regulation of interleukin-10 and interleukin-10 receptor in rat astroglial and microglial cells. Eur. J. Neurosci. 16, 1175–1185.
Mizuno T., Sawada M., Marunouchi T., Suzumura A. 1994. Production of interleukin-10 by mouse glial cells in culture. Biochem. Biophys. Res. Commun. 205, 1907–1915.
Rasley A., Tranguch S.L., Rati D.M., Marriott I. 2006. Murine glia express the immunosuppressive cytokine, interleukin-10, following exposure to Borrelia burgdorferi or Neisseria meningitidis. Glia. 53. 583–592.
Fouda A.Y., Kozak A., Alhusban A., Switzer J.A., Fagan S.C. 2013. Anti-inflammatory IL-10 is upregulated in both hemispheres after experimental ischemic stroke: Hypertension blunts the response. Exp. Transl. Stroke Med. 5, 12.
Font-Nieves M., Sans-Fons M.G., Gorina R., Bonfill-Teixidor E., Salas-Pérdomo A., Márquez-Kisinousky L., Santalucia T., Planas A.M. 2012. Induction of COX-2 enzyme and down-regulation of COX-1 expression by lipopolysaccharide (LPS) control prostaglandin E2 production in astrocytes. J. Biol. Chem. 287, 6454–6468.
Kipper-Galperin M., Galilly R., Danenberg H.D., Brenner T. 1999. Dehydroepiandrosterone selectively inhibits production of tumor necrosis factor alpha and interleukin-6 [correction of interlukin-6] in astrocytes. Int. J. Dev. Neurosci. 17, 765–775.
Di Santo E., Foddi M.C., Ricciardi-Castagnoli P., Mennini T., Ghezzi P. 1996. DHEAS inhibits TNF production in monocytes, astrocytes and microglial cells. Neuroimmunomodulation. 3, 285–288.
Dulos J., Verbraak E., Bagchus W.M., Boots A.M.H., Kaptein A. 2004. Severity of murine collagen-induced arthritis correlates with increased CYP7B activity: Enhancement of dehydroepiandrosterone metabolism by interleukin-1? Arthritis Rheum. 50, 3346–3353.
Morfin R., Courchay G. 1994. Pregnenolone and dehydroepiandrosterone as precursors of native 7-hydroxylated metabolites which increase the immune response in mice. J. Steroid Biochem. Mol. Biol. 50, 91–100.
Karishma K.K., Herbert J. 2002. Dehydroepiandrosterone (DHEA) stimulates neurogenesis in the hippocampus of the rat, promotes survival of newly formed neurons and prevents corticosterone-induced suppression. Eur. J. Neurosci. 16, 445–453.
Chen F., Knecht K., Birzin E., Fisher J., Wilkinson H., Mojena M., Moreno C.T., Schmidt A., Harada S., Freedman L.P., Reszka A.A. 2005. Direct agonist/antagonist functions of dehydroepiandrosterone. Endocrinology. 146, 4568–4576.
Liu D., Dillon J.S. 2004. Dehydroepiandrosterone stimulates nitric oxide release in vascular endothelial cells: Evidence for a cell surface receptor. Steroids. 69, 279–289.
Karbowska J., Kochan Z. 2013. Effects of DHEA on metabolic and endocrine functions of adipose tissue. Horm. Mol. Biol. Clin. Investig. 14, 65–74.
Li J., Papadopoulos V., Vihma V. 2015. Steroid biosynthesis in adipose tissue. Steroids. 103, 89–104.
Kipp M., Hochstrasser T., Schmitz C., Beyer C. 2016. Female sex steroids and glia cells: Impact on multiple sclerosis lesion formation and fine tuning of the local neurodegenerative cellular network. Neurosci. Biobehav. Rev. 67, 125–136.
Loram L.C., Sholar P.W., Taylor F.R., Wiesler J.L., Babb J.A., Strand K.A., Berkelhammer D., Day H.E, Maier S.F., Watkins L.R. 2012. Sex and estradiol influence on glial pro-inflammatory responses to lipopolysaccharide in rats. Psychoneuroendocrinology. 37, 1688–1699.
De Marinis E., Acaz-Fonseca E., Arevalo M.A., Ascenzi P., Fiocchetti M., Marino M., Garcia-Segura L.M. 2013. 17-beta-estradiol anti-inflammatory effects in primary astrocytes require oestrogen receptor-beta-mediated neuroglobin up-regulation. J. Neuroendocrinol. 25, 260–270.
Santos-Galindo M., Acaz-Fonseca E., Bellini M.J., Garcia-Segura L.M. 2011. Sex differences in the inflammatory response of primary astrocytes to lipopolysaccharide. Biol. Sex Differ. 2, 7.
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Original Russian Text © S.M. Buyanova, D.V. Chistyakov, A.A. Astakhova, M.G. Sergeeva, 2017, published in Biologicheskie Membrany, 2017, Vol. 34, No. 5, pp. 22–29.
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Buyanova, S.M., Chistyakov, D.V., Astakhova, A.A. et al. The effect of dehydroepiandrosterone on inflammatory response of astroglial cells. Biochem. Moscow Suppl. Ser. A 11, 304–310 (2017). https://doi.org/10.1134/S199074781704002X
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DOI: https://doi.org/10.1134/S199074781704002X