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Abstract

Platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) and its receptor are known to play important roles in modulating neuronal plasticity and inflammatory responses, particularly during neuronal injury. PAF receptors are widespread in different brain regions and are present on the cell surface as well as in intracellular membrane compartments. Astrocytes are immune active cells and are responsive to cytokines, which stimulate signaling cascades leading to transcriptional activation of genes and protein synthesis. Our recent studies indicate the ability of cytokines, e.g., tumor necrosis factor-alpha (TNFalpha), interleukin-1beta (IL-1beta) and interferon-gamma (IFNgamma), to induce the inducible nitric oxide (iNOS) and secretory phospholipase A2 (sPLA2) genes in immortalized astrocytes (DITNC) (Li et al., J. Interferon and Cytokine Res. 19: 121-127. 1999). The main objective for this study is to examine the effects of PAF antagonists on cytokine induction of iNOS and sPLA2 in these cells. Results show that BN50730, a synthetic PAF antagonist, but not BN52021, a natural PAF antagonist (ginkolide B) can dose-dependently inhibit cytokine induction of NO production and sPLA2 release. Inhibition of NO production by BN50730 corroborated well with the decrease in iNOS protein and mRNA levels as well as binding of NF-kappaB STAT- 1 to DNA, suggesting that BN50730 action is upstream of the transcriptional process. These results are in agreement with the role of intracellular PAF in regulating the cytokine signaling cascade in astrocytes and further suggest the possible use of BN50730 as a therapeutic agent for suppressing the inflammatory pathways elicited by cytokines.

Pro-inflammatory cytokines and lipopolysaccharide induce changes in cell morphology, and upregulation of ERK1/2, iNOS and sPLA2-IIA expression in astrocytes and microglia

“…In primary and immortalized astrocytes of rat origin, induction of sPLA2-IIA can be mediated independently by TNFα and IL-1β, without the involvement of IFNγ [21,22,28,36]. Since BV-2 cells are of murine origin, it is not surprising that these cells lack the ability to induce sPLA2-IIA upon exposure to cytokines.…”

Astrocytes regulate α-secretase-cleaved soluble amyloid precursor protein secretion in neuronal cells: Involvement of group IIA secretory phospholipase A2

“…It has been shown that when stimulated by cytokines such as TNF α and IL-1β, DITNC astrocytes showed increased mRNA expression of sPLA 2 -IIA (Li et al, 1999; Wang and Sun, 2000; Jensen et al, 2009). In this study, we first determined whether stimulation of DITNC astrocytes with TNF α and IL-1β induced sPLA 2 -IIA secretion.…”

“…Increase in sPLA 2 -IIA mRNA was also observed in the rat brain after focal cerebral ischemia (Lin et al, 2004). In studies with astrocytes, pro-inflammation cytokines were shown to increase sPLA 2 -IIA mRNA expression through activation of the NF-jB transcription pathway (Li et al, 1999; Wang and Sun, 2000; Jensen et al, 2009). sPLA 2 -IIA from astrocytes was linked to the production of reactive oxygen species and apoptosis through activation of the superoxide producing enzyme NADPH oxidase in neurons (Yagami et al, 2014).…”

“…sPLA 2 -IIA also has antibacterial functions (Harwig et al, 1995; Weinrauch et al, 1996) and increased production has been linked to inflammatory diseases, including rheumatoid arthritis and Alzheimer’s disease (AD) (Hurt-Camejo et al, 2001; Sun et al, 2004, 2007; Jia et al, 2005; Moses et al, 2006). In cell culture systems, upregulation of sPLA 2 -IIA mRNA expression has been shown in astrocytes stimulated with pro-inflammatory cytokines, processes that activate the NF-κB pathway (Li et al, 1999; Wang and Sun, 2000; Jensen et al, 2009). Using non-specific PLA 2 inhibitors, Cho et al (2006) showed that PLA 2 s affect the proteolytic process of amyloid precursor protein (APP), which produces either neurotoxic amyloid-β peptide (Aβ) (Vassar, 2004) or neurotrophic and neuroprotective α-secretase-cleaved soluble APP (sAPP α ) (Esch et al, 1990; Allinson et al, 2003; Thornton et al, 2006).…”