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Regulation of cyclooxygenase 2 expression by agonists of PPAR nuclear receptors in the model of endotoxin tolerance in astrocytes

Abstract

Endotoxin tolerance (ET) represents a state of an altered immune response induced by multiple stimulations of a cell, a tissue, or an organism with lipopolysaccharide. Characteristics of ET include downregulation of induction of proinflammatory genes (TNFα, IL6, and others) and enhancement of induction of antiinflammatory genes (IL10, TGFβ). ET generally has protective functions; nevertheless, it might result in a state of innate immune deficiency and cause negative outcomes. A current issue is the search for the mechanisms controlling the level of inflammation in the course of endotoxin tolerance. In this work, we investigated the change in cyclooxygenase 2 (Cox2) expression in the model of endotoxin tolerance in astrocytes and analyzed the possibility of regulating this process applying nuclear receptor PPAR agonists. Our results indicate that: 1) endotoxin tolerance can be induced in astrocytes and results in TNFα and Cox2 mRNA induction decrease upon secondary stimulation; 2) tolerance is revealed on the level of TNFα release and Cox2 protein expression; 3) PPAR agonists GW7647, L-165041, and rosiglitazone control Cox2 mRNA expression levels under conditions of endotoxin tolerance. In particular, rosiglitazone (a PPARγ agonist) induces Cox2 mRNA expression, while GW7647 (a PPARα agonist) and L-165041 (a PPARβ agonist) suppress the expression. Our results demonstrate that Cox2 can be upand downregulated during endotoxin tolerance in astrocytes, and PPAR agonists might be effective for controlling this target under conditions of multiple proinflammatory stimulations of brain tissues with endotoxin.

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Abbreviations

CNS:

central nervous tissue

Cox2:

cyclooxygenase 2

ET:

endotoxin tolerance

IL6:

interleukin 6

LDH:

lactate dehydrogenase

LPS:

lipopolysaccharide (endotoxin)

PPAR:

peroxisome proliferator-activated receptors

TNFα:

tumor necrosis factor alpha

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Correspondence to A. A. Astakhova.

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Published in Russian in Biokhimiya, 2015, Vol. 80, No. 10, pp. 1532-1541.

Originally published in Biochemistry (Moscow) On-Line Papers in Press, as Manuscript BM15-110, August 2, 2015.

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Astakhova, A.A., Chistyakov, D.V., Pankevich, E.V. et al. Regulation of cyclooxygenase 2 expression by agonists of PPAR nuclear receptors in the model of endotoxin tolerance in astrocytes. Biochemistry Moscow 80, 1262–1270 (2015). https://doi.org/10.1134/S0006297915100065

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  • DOI: https://doi.org/10.1134/S0006297915100065

Keywords

  • cyclooxygenase 2
  • nuclear receptors
  • PPAR agonists
  • rosiglitazone
  • endotoxin tolerance
  • innate immunity
  • astrocytes