Expression and Regulation of Cyclooxygenase‐2 in Rat Microglia

Abstract

Increased levels of prostanoids have been implicated in various neuropathological diseases, although little is known about their cellular sources inside the brain. In this study. we analyzed the expression of cyclooxygenase-2 (COX-2), a key enzyme in arachidonic acid metabolism, in rat microglia. COX-2 mRNA and protein as well as prostaglandin E, formation were almost undetectable in unstimulated microglial cultures but were found to be strongly upregulated in response to lipopolysaccharide. However, in contrast to most peripheral cells, proinflammatory cytokines such as tumor necrosis factor cr, interleukin-I [ j or interleukin-6 failed to markedly induce COX-2 expression. Similar effects were observed by analyzing transcription nuclear factor-lc B (NF-KB) which was strongly activated in microglia by lipopolysaccharide but not by incubation with cytokines. Moreover, known inhibitors of NF-KB activation, such as dexamethasone and the antioxidant pyrrolidine dithiocarbamate, as well as the protein kinase C (PKC) inhibitor Go6976, strongly reduced lipopolysaccharide-induced COX-2 transcription, indicating the involvement of NF-h-B and PKC in COX-2 expression. Our results suggest that microglia may represent an important source of prostanoids in the brain, thus reinforcing their prominent role in cerebral inflammatory processes.

Effect of Acute Systemic Inflammatory Response and Cytokines on the Transcription of the Genes Encoding Cyclooxygenase Enzymes (COX‐1 and COX‐2) in the Rat Brain

“…These results suggest that the promflammatory cytokine IL-6 does not, by itself (when itijected into the circulation), have the ability to trigger COX-2 gene transcription in the rat brain, and the effects of systemic inflammation and circulating IL-i /3 in this response are likely to be IL-6 independent. The lack of stimulatory influence of IL-6 on COX-2 gene expression has also been reported in different in vitro models using rat microglial (Bauer et al, 1997) and primary munine astrocyte cultures (O'Banion et al, 1996). This contrasts with a recent study showing that COX-2 mRNA is inducible by IL-6 in normal human articular chondrocytes (Geng et al, 1995).…”

Induction of Cyclooxygenase-2 Accounts for Restraint Stress-Induced Oxidative Status in Rat Brain

“…It is well known that basic gene induction mechanisms, including increase in NFkB-DNA binding, is fundamental in COX-2 expression in neurodegenerative disorders (Lukiw and Bazan, 1998). Furthermore, known inhibitors of NF-kB activation, including PDTC and PKC inhibitors, strongly reduced COX-2 transcription (Bauer et al, 1997;Callejas et al, 1999). The effect of PDTC decreasing stress-induced accumulation of PGE 2 and COX-2 protein described in this paper suggests the involvement of NF-kB mechanisms.…”

Differential activation of subtype purinergic receptors modulates Ca2+ mobilization and COX‐2 in human microglia

“…The expression of COX-2 is markedly enhanced in inflamed tissue and is responsible for the production of prostanoid mediators of inflammation, including prostaglandins (Seibert et al, 1994;Smith and DeWitt, 1995). Inflammatory stimuli such as lipopolysaccharide (LPS) and cytokines such as TNF␣ and IL-1␤ have been found to enhance COX-2 expressions in microglia (Minghetti and Levi, 1995;Bauer et al, 1997). In pathological conditions, elevated COX-2 expressions have been observed in AD brain and ALS spinal cord (Ho et al, 1999;Yasojima et al, 1999Yasojima et al, , 2001.…”