Interleukin‐1 beta activates expression of cyclooxygenase‐2 and inducible nitric oxide synthase in primary hippocampal neuronal culture: Platelet‐activating factor as a preferential mediator of cyclooxygenase‐2 expression

Abstract

Interleukin-1 beta (IL-1beta) is an inflammatory cytokine whose expression is elevated in brain during seizures, ischemia, and injury. Expression of IL-1beta and its receptor can also be observed in normal brain. Platelet-activating factor (PAF) is also a dual mediator that promotes neuronal plasticity responses as well as inflammation. We have determined the role of PAF in the regulation of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) genes by IL-1beta in rat primary hippocampal cultures. As assessed by reverse transcriptase/polymerase chain reaction (RT/PCR), recombinant mouse IL-1beta (1 nM) led to an induction of COX-2 mRNA which peaked at 2 hours, declined to baseline levels by 4 hours, began to rise again by 6 hours, and remained elevated at 24 hours post-treatment. iNOS mRNA was also induced, but unlike COX-2, its abundance peaked at 4 hours and decreased by 6 hours to a plateau lasting through 24 hours. Pretreatment with PAF antagonist BN50730 blocked induction of COX-2 mRNA by 2-hour IL-1beta treatment, and 2-hour treatment with the PAF analog mcPAF mimicked the effects of IL-1beta on COX-2 mRNA levels. Following injury, synaptic plasticity changes may be affected by IL-1beta-PAF-COX-2 neuronal signaling.

Central and Systemic Endotoxin Challenges Exacerbate the Local Inflammatory Response and Increase Neuronal Death during Chronic Neurodegeneration

“…This chemokine is induced by IL-1␤ (Xu et al, 1995), and neutrophil infiltration to the CNS can be blocked by neutralization of either IL-1␤ or the rat equivalent CXC chemokine, cytokine-induced neutrophil chemoattractant 1 (Anthony et al, 1998). IL-1␤ expression is also known to induce iNOS (Serou et al, 1999) and thus may underlie the microglial expression of iNOS seen here. The production of the oxidant NO has been demonstrated previously to be involved in neuronal death and damage (Takeuchi et al, 1998;Smith et al, 2001).…”

“…That a less severe inflammatory challenge is also sufficient to induce acute neuronal death may have important consequences for patients with chronic neurodegenerative disease subsequently exposed to common low-grade peripheral infections. Proinflammatory cytokines, including IL-1␤ and TNF␣, are known to exacerbate neuronal damage in acute injury models (Stroemer and Rothwell, 1998), and this may occur through IL-1␤-activated pathways such as induction of inducible COX-2 (Serou et al, 1999), tissue plasminogen activator (Eberhardt et al, 2002), iNOS (Tamatani et al, 1998), and increased synthesis of the damaging reactive oxygen species superoxide and peroxynitrite (Fink et al, 1999). There is already clinical evidence that infections are deleterious in dementia.…”

Cerebrovascular Inflammation Following Subarachnoid Hemorrhage

“…Experimentally, it has also been found that ET-1 (see later discussion) may stimulate the expression of COX-2 (116). IL-1b also induces COX-2 expression (117) and this effect is antagonised by a PAF antagonist.…”

Nitric oxide (NO) modulation of PAF‐induced cardiopulmonary action: interaction between NO synthase and cyclo‐oxygenase‐2 pathways

“…The latter is expressed in a variety of tissues, including human pulmonary epithelial cells and rat lungs (Uhlig et al, 1996), in response to various stimuli (DeWitt & Smith, 1995). Since the expression of COX-2 has also been recently found in response to PAF in experiments on cell cultures from various tissues (Alvi et al, 1999;Bazan et al, 1997;Serou et al, 1999), a further purpose of this study was to verify whether the COX-2 isoform contributes to PAF-induced cardiopulmonary actions.…”