Jh. Wang et Gy. Sun, Platelet activating factor (PAF) antagonists on cytokine induction of iNOSand sPLA(2) in immortalized astrocytes (DITNC), NEUROCHEM R, 25(5), 2000, pp. 613-619
Platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocho
line) and its receptor are known to play important roles in modulating neur
onal plasticity and inflammatory responses, particularly during neuronal in
jury. PAF receptors are widespread in different brain regions and are prese
nt on the cell surface as well as in intracellular membrane compartments. A
strocytes are immune active cells and are responsive to cytokines, which st
imulate signaling cascades leading to transcriptional activation of genes a
nd protein synthesis. Our recent studies indicate the ability of cytokines,
e.g., tumor necrosis factor-alpha (TNF alpha), interleukin-1 beta (IL-1 be
ta) and interferon-gamma (IFN gamma), to induce the inducible nitric oxide
(iNOS) and secretory phospholipase A(2) (sPLA(2)) genes in immortalized ast
rocytes (DITNC) (Li et al., J. Interferon and Cytokine Res. 19: 121-127. 19
99). The main objective for this study is to examine the effects of PAF ant
agonists on cytokine induction of iNOS and sPLA(2) in these cells. Results
show that BN50730, a synthetic PAF antagonist, but not BN52021, a natural P
AF antagonist (ginkolide B) can dose-dependently inhibit cytokine induction
of NO production and sPLA(2) release. Inhibition of NO production by BN507
30 corroborated well with the decrease in iNOS protein and mRNA levels as w
ell as binding of NF-kappa B and STAT-1 to DNA, suggesting that BN50730 act
ion is upstream of the transcriptional process. These results are in agreem
ent 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 cy
tokines.