The roles of arachidonic acid metabol in the pathogenesis of inflammatory diseases in childhood: Regulation of related enzymes by various cytokines

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A series of enzymes which are responsible for the synthesis of prostaglandins(PGs), thromboxane(TX) and leukotriens(LTs) are activated in a variety of allergic and inflammatory disease in childhood. One of the possible regulatory mechanisms is a transcriptional up-regulation by various cytokines and inflammatory mediators at the transcriptional and/or translational levels of each enzyme. In this study, we have investigated up-regulatory mechanisms of cytosolic PLA2, cyclooxygenase(COX)-1, COX -2, 5-lipoxygenase (5-LO), LTC4 synthase (LTC4syn), LTA4 hydrolase and 5-LO activating protein (FLAP) in PMNs and HL-60 cells by using RT-PCR and Northern blotting techniques. In PMNs, the synthesis of LTB4 and TXB2 was increased by the stimulation with IL-3 and GM/CSF for 30-60 min, the production was then decreased. After several hours, the synthesis of TXB2 but not LTB4 was increased again, which was associated with enhanced expression of COX-2 mRNA. IL-8 temporarily increased the synthesis of LTB4 after 60 min stimulation, indicating a priming effect on 5-LO or LTA4 hydrolase. LTB4 synthesis was enhanced by IL-4 and IL-13 after 6 hour incubation, which was associated the enhanced expression of LTA4 hydrolase mRNA. Lipopolysaccharide(LPS), a bacterial endotoxin, increased the production of TXB2 by new induction of cPLA2 and COX-2 in PMNs. In DMSO-treated HL-60 cells, the synthesis of LTB4 and LTC4 was increased by transcriptionaly up-regulating 5-LO, LTC4syn and LTA4 hydrolase. We also investigated how anti-inflammatory and anti-allergy medicines modulate these enzyme activities.