PubMed · 15209137
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D Clissold, C Thickitt. 1994. Recent eicosanoid chemistry.. https://doi.org/10.1039/np9941100621
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We examined the role of prostaglandin D(2) (PGD(2)) in the expression of vascular cell adhesion molecule-1 (VCAM)-1 following interleukin-1beta (IL-1) stimulation in human umbilical vein endothelial cells (HUVEC) transfected with lipocaline-type PGD(2) synthase (L-PGDS) genes. HUVEC were isolated from human umbilical vein and incubated with 20 U/ml IL-1 and various concentrations of authentic PGD(2). The isolated HUVEC were also transfected with L-PGDS genes by electroporation. The L-PGDS-transfected HUVEC were used to investigate the role of endogenous PGD(2) in IL-1-stimulated VCAM-1 biosynthesis. We also used an anti-PGD(2) antibody to examine whether an intracrine mechanism was involved in VCAM-1 production. PGD(2) and VCAM-1 levels were determined by radio- and cell surface enzyme-immunoassay, respectively. VCAM-1 mRNA was assessed by RT-PCR. IL-1-stimulated VCAM-1 expression by HUVEC was dose-dependently inhibited by authentic PGD(2). L-PGDS gene-transfected HUVEC produced more PGD(2) than HUVEC transfected with the reporter gene alone. IL-1 induced increases in VCAM-1 expression in HUVEC transfected with reporter genes alone. However, this effect was significantly attenuated in the case of IL-1 stimulation of HUVEC transfected with L-PGDS genes, and accompanied by an apparent suppression of VCAM-1 mRNA expression. Neutralization of extracellular PGD(2) by anti-PGD(2)-specific antibody influenced neither VCAM-1 mRNA expression nor VCAM-1 biosynthesis. In conclusion, HUVEC transfected with L-PGDS genes showed increased PGD(2) synthesis. This increase was associated with attenuation of both VCAM-1 expression and VCAM-1 mRNA expression. The results suggest that endogenous PGD(2) decreases VCAM-1 expression and VCAM-1 mRNA expression, probably through an intracrine mechanism.
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BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are implicated in several diseases showing altered tissue and leukocyte eicosanoid patterns, such as nasal polyposis and asthma. NSAIDs are also associated with gastrointestinal lesions, but it is unknown whether there is an altered eicosanoid pattern. MATERIAL/METHODS: The ex vivo modulated syntheses of prostaglandin E2 (PGE2) and peptido-leukotrienes (pLT) by leukocytes from 41 patients with gastroduodenal ulcer were compared with those of 61 healthy controls. Samples were incubated with diluent, arachidonic acid, or acetylsalicylic acid. The individual syntheses of PGE2 and pLT were quantified using competitive enzyme-immuno-assays followed by calculation of individual eicosanoid patterns. RESULTS: Controls synthesized approximately 4.9-fold whereas patients only approximately 2.9-fold more PGE2 than pLT due to higher basal synthesis of pLT (67 and 125 pg/ml, respectively). The baseline PGE2/pLT ratio was slightly higher in patients (6.1) than in controls (5.7). The arachidonic acid-induced PGE2/pLT ratio in patients (14.2) was significantly higher than in controls (3.3). The acetylsalicylic acid-induced PGE2/pLT ratio in patients (3.5) was significantly lower than in controls (8.3) due to diminished PGE2 and elevated pLT. Integrated individual PGE2 and pLT values revealed a highly significantly altered eicosanoid pattern score in approximately 95% patients and approximately 12% controls. CONCLUSIONS: There is strong evidence of an altered eicosanoid pattern generated by leukocytes of gastroduodenal ulcer patients, which became obvious upon in vitro modulation by arachidonic or acetylsalicylic acid. The phenomenon of an abnormal eicosanoid pattern in gastroduodenal ulcer is yet not fully understood, but may have implications in pathophysiology and diagnostics.