Article

Induction of COX‐2 and PGE2 biosynthesis by IL‐1β is mediated by PKC and mitogen‐activated protein kinases in murine astrocytes

British Journal of Pharmacology (Impact Factor: 4.99). 08/2000; 131(1):152 - 159. DOI: 10.1038/sj.bjp.0703557

ABSTRACT Interleukin-1 (IL-1) is an important mediator of immunoinflammatory responses in the brain. In the present study, we examined whether prostaglandin E2 (PGE2) production after IL-1β stimulation is dependent upon activation of protein kinases in astroglial cells.Astrocyte cultures stimulated with IL-1β or the phorbol ester, PMA significantly increased PGE2 secretion. The stimulatory action of IL-1β on PGE2 production was totally abolished by NS-398, a specific inhibitor of cyclo-oxygenase-2 activity, as well as by the protein synthesis inhibitor cycloheximide, and the glucocorticoid dexamethasone. Furthermore, IL-1β induced the expression of COX-2 mRNA. This occurred early at 2 h, with a maximum at 4 h and declined at 12 h. IL-1 β treatment also induced the expression of COX-2 protein as determined by immunoblot analysis. In that case the expression of the protein remained high at least up to 12 h.Treatment of cells with protein kinase C inhibitors (H-7, bisindolylmaleimide and calphostin C) inhibited IL-1β stimulation of PGE2. In addition, PKC-depleted astrocyte cultures by overnight treatment with PMA no longer responded to PMA or IL-1. The ablation of the effects of PMA and IL-1β on PGE2 production, likely results from down-regulation of phorbol ester sensitive-PKC isoenzymes. Immunoblot analysis demonstrated the translocation of the conventional isoform cPKC-α from cytosol to membrane following treatment with IL-1β.In addition, IL-1β treatment led to activation of extracellular signal-regulated kinase (ERK1/2) and p38 subgroups of MAP kinases in astroglial cells. Interestingly, the inhibition of ERK kinase with PD 98059, as well as the inhibition of p38 MAPK with SB 203580, prevented IL-1β-induced PGE2 release.ERK1/2 activation by IL-1β was sensitive to inhibition by the PKC inhibitor bisindolylmaleimide suggesting that ERK phosphorylation is a downstream signal of PKC activation.These results suggest key roles for PKC as well as for ERK1/2 and p38 MAP kinase cascades in the biosynthesis of PGE2, likely by regulating the induction of cyclo-oxygenase-2, in IL-1β-stimulated astroglial cells.British Journal of Pharmacology (2000) 131, 152–159; doi:10.1038/sj.bjp.0703557

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Available from: Francisco Molina-Holgado, Aug 04, 2015
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    • "Of these, the IL-1β isoform is by far the most often reported in TBI. IL-1β is a pro-inflammatory cytokine and has been implicated in the release of phospholipase-2 (PLA2), prostaglandins, and the activation of cyclooxygenase-2 (COX-2; Chung and Benveniste, 1990; Aloisi et al., 1992; Molina-Holgado et al., 2000; Rothwell, 2003). Furthermore, the primary mechanism of action for IL- 1β is believed to be the regulation of release of other cytokines. "
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    • "In all of these diseases, astrocytes and microglia are the major sources of COX-2 and PGE 2 (Mingetti et al, 1999; Molina-Holgado et al, 2000). Virus infections in general tend to stimulate COX-2 expression (Murono et al, 2001; Janelle et al, 2002; Seymour et al, 2002), and inhibitors of COX-2 activity attenuate virus replication (Chen et al, 2000; Zhu et al, 2002), suggesting that COX-2 activation and the cellular events that follow are important determinants governing viral replication and the spread of infection and cellular damage in the CNS. "
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    • "First, astrocyte–monocyte cocultures are an established in vitro model and have been used extensively in the study of HIV-1-associated dementia (Genis et al., 1992; Fiala et al., 1996; Pereira et al., 2001) and chemokine expression in the CNS (Andjelkovic et al., 2000). Second, the capacity of astrocytes to produce PGE 2 after stimulation with IL-1␤ or TNF-␣ has been well documented (Janabi et al., 1999; Pistritto et al., 1999; Molina-Holgado et al., 2000). Third, although astrocytes produce copious amounts of PGE 2 , we have found that they do not express OSM in response to IL-1␤ or PGE 2 stimulation (Fig. 8 D) (data not shown). "
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