Interleukin‐1β Induces Prostaglandin G/H Synthase‐2 (Cyclooxygenase‐2) in Primary Murine Astrocyte Cultures

Abstract

Activation of glial cells and the consequent release of cytokines, proteins, and other intercellular signaling molecules is a well‐recognized phenomenon in brain injury and neurodegenerative disease. We and others have previously described an inducible prostaglandin G/H synthase, known as PGHS‐2 or cyclooxygenase‐2, that is up‐regulated in many cell systems by cytokines and growth factors and down‐regulated by glucocorticoid hormones. In cultured mouse astrocytes we observed increased production of prostaglandin E2 (PGE2) after stimulation with either interleukin‐1β (IL‐1β) or the protein kinase C activator phorbol 12‐myristate 13‐acetate (TPA). This increase in PGE2 content was blocked by pretreatment with dexamethasone and correlated with increases in cyclooxygenase activity measured at 4 h. Northern blots revealed concomitant increases in PGHS‐2 mRNA levels that peaked at 2 h and were dependent on the dosage of IL‐1β. Dexamethasone inhibited this induction of PGHS‐2 mRNA by IL‐1β. TPA, basic fibroblast growth factor, and the proinflammatory factors tumor necrosis factor α and lipopolysaccharide, but not interleukin‐6, also stimulated PGHS‐2 mRNA expression. Relative to IL‐1β, the greater increases in PGE2 production and cyclooxygenase activity caused by TPA correlated with a greater induction of PGHS‐2 mRNA. Furthermore, NS‐398, a specific inhibitor of cyclooxygenase‐2, blocked >80% of the cyclooxygenase activity in TPA‐treated astrocytes. These findings indicate that increased expression of PGHS‐2 contributes to prostaglandin production in cultured astrocytes exposed to cytokines and other factors.

Prostaglandins are necessary and sufficient to induce contextual fear learning impairments after interleukin-1 beta injections into the dorsal hippocampus

“…This data is congruent with previous studies suggesting that COX-2 is involved. Classically, COX-2 is considered the inducible form of COX and IL-1β strongly upregulates COX-2 mRNA within brain glial cells (O'Banion et al, 1996). Furthermore, selective COX-2 inhibitors prevent impairments from LPS, immobilization stress, traumatic brain injury, and aging, although to our knowledge selective COX-1 inhibitors have never been examined (Jain et al, 2002;Mesches et al, 2004;Gopez et al, 2005;Bishnoi et al, 2005;Dhir et al, 2006).…”

“…Indeed, circulating IL-1β, which has low diffusion across the blood brain barrier, has been shown to upregulate COX activity within brain vascular endothelium causing the release of PGs into the brain parenchyma (Monica et al, 2001). IL-1β within the brain parenchyma can also cause the release of PGs from brain glial cells (O'Banion et al, 1996). Thus, PGs are in a position to mediate some of the effects of IL-1β within the brain.…”

Role of cyclic AMP responsive element in the UVB induction of cyclooxygenase-2 transcription in human keratinocytes

“…COX-1 is expressed constitutively in most cell types and is involved in regulation of renal and vascular homeostasis and protection of the gastrointestinal tract (Kam and See, 2000). COX-2 has low basal expression in most tissues, but is induced by tumor promoters (Kujubu et al, 1991), growth factors (Moatter and Gerritsen, 1992), cytokines (O'Banion et al, 1996) and endotoxins (O'Sullivan et al, 1992).…”

Transforming Growth Factor β1 Regulates the Expression of Cyclooxygenase in Cultured Cortical Astrocytes and Neurons

“…Accordingly, the total protein in each sample was determined by the method of Lowry et al (1951), and the ratio of picograms of PGE2 per microgram of protein was calculated. Four replicates for each treatment group were processed.To examine the activity of COX, we assessed the TGFß1-mediated change in the amount of PGE2 by using the procedure of O'Banion et al (1996). Prostaglandin production is determined by the availability of free AA and COX activity.…”