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Induction of COX-2 enzyme and down-regulation of COX-1 expression by lipopolysaccharide (LPS) control prostaglandin E2 production in astrocytes.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2012 Feb 24; Vol. 287 (9), pp. 6454-68. Date of Electronic Publication: 2012 Jan 04. - Publication Year :
- 2012
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Abstract
- Pathological conditions and pro-inflammatory stimuli in the brain induce cyclooxygenase-2 (COX-2), a key enzyme in arachidonic acid metabolism mediating the production of prostanoids that, among other actions, have strong vasoactive properties. Although low basal cerebral COX-2 expression has been reported, COX-2 is strongly induced by pro-inflammatory challenges, whereas COX-1 is constitutively expressed. However, the contribution of these enzymes in prostanoid formation varies depending on the stimuli and cell type. Astrocyte feet surround cerebral microvessels and release molecules that can trigger vascular responses. Here, we investigate the regulation of COX-2 induction and its role in prostanoid generation after a pro-inflammatory challenge with the bacterial lipopolysaccharide (LPS) in astroglia. Intracerebral administration of LPS in rodents induced strong COX-2 expression mainly in astroglia and microglia, whereas COX-1 expression was predominant in microglia and did not increase. In cultured astrocytes, LPS strongly induced COX-2 and microsomal prostaglandin-E(2) (PGE(2)) synthase-1, mediated by the MyD88-dependent NFκB pathway and influenced by mitogen-activated protein kinase pathways. Studies in COX-deficient cells and using COX inhibitors demonstrated that COX-2 mediated the high production of PGE(2) and, to a lesser extent, other prostanoids after LPS. In contrast, LPS down-regulated COX-1 in an MyD88-dependent fashion, and COX-1 deficiency increased PGE(2) production after LPS. The results show that astrocytes respond to LPS by a COX-2-dependent production of prostanoids, mainly vasoactive PGE(2), and suggest that the coordinated down-regulation of COX-1 facilitates PGE(2) production after TLR-4 activation. These effects might induce cerebral blood flow responses to brain inflammation.
- Subjects :
- Animals
Astrocytes cytology
Astrocytes drug effects
Cells, Cultured
Cyclooxygenase 1 genetics
Cyclooxygenase 2 genetics
Cyclooxygenase 2 Inhibitors pharmacology
Down-Regulation physiology
Gene Expression Regulation, Enzymologic drug effects
Gene Expression Regulation, Enzymologic physiology
JNK Mitogen-Activated Protein Kinases metabolism
Male
Membrane Proteins genetics
Mice
Mice, Inbred C57BL
Mice, Knockout
Microglia cytology
Microglia drug effects
Microglia enzymology
Myeloid Differentiation Factor 88 genetics
RNA, Small Interfering pharmacology
Rats
Rats, Sprague-Dawley
p38 Mitogen-Activated Protein Kinases metabolism
Astrocytes enzymology
Cyclooxygenase 1 metabolism
Cyclooxygenase 2 metabolism
Dinoprostone biosynthesis
Lipopolysaccharides pharmacology
Membrane Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 287
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 22219191
- Full Text :
- https://doi.org/10.1074/jbc.M111.327874