Omega-3 fatty acids and decidual cell prostaglandin production in response to the inflammatory cytokine IL-1beta.

OBJECTIVE: The objective of this study was to determine the effect of omega-3 fatty acids (eicosapentaenoic acid [EPA]; docosahexaenoic acid [DHA]) on prostaglandin production and prostanoid enzyme expression in cultured decidual cells exposed to interleukin-1beta (IL-1beta), a cytokine that plays a major role in inflammation. STUDY DESIGN: Decidua was obtained from human placentas of nonlaboring patients at term cesarean delivery (N = 6) and cultured by using standard cell culture techniques. Cells were preincubated in defined media with various concentrations of vehicle, DHA, or EPA for 1 hour. IL-1beta (10 ng/mL) was then added to the media, and experiments were terminated 12 hours after exposure to IL-1beta. Prostaglandin E2 (PGE2) and PGF2alpha concentrations in conditioned media were measured by enzyme-linked immunosorbent assay; cyclooxygenase-1 (COX-1), COX-2, microsomal prostaglandin E synthase (mPGES)-1, mPGES-2, and 15-hydroxy prostaglandin dehydrogenase (PGDH) expression were quantified by real-time polymerase chain reaction and immunoblotting. Groups were compared with the use of Student t test, with significance defined as P < .05. RESULTS: Preincubation with DHA decreased prostaglandin production by up to 80% when compared with controls. DHA decreased both mPGES-1 and -2 messenger RNA expression by approximately 50% (P = .02). Preincubation in DHA or EPA had no effect on COX-1, COX-2, and PGDH messenger RNA or protein expression. CONCLUSION: Under conditions simulating inflammation, supplementation with omega-3 fatty acids decreases PGE2 and PGF2alpha production in cultured decidual cells. The reduction in prostaglandin production was associated with a decreased expression of mPGES-1 and -2. These findings suggest a mechanism by which omega-3 fatty acid supplementation decreases the incidence of preterm birth in high-risk patients.

LPA-induced epithelial ovarian cancer (EOC) in vitro invasion and migration are mediated by VEGF receptor-2 (VEGF-R2).

OBJECTIVE: Lysophosphatidic acid (LPA) stimulates ovarian tumor growth partially via induction of VEGF expression through transcriptional activation. Previous studies have shown that LPA induces epithelial ovarian cancer (EOC) in vitro metastasis. In this study, we examined the role of VEGF in LPA-induced EOC invasion and migration and underlying mechanisms. METHODS: The invasiveness of DOV13 cells was determined by in vitro basement membrane Matrigel invasion assay. Ovarian carcinoma cellular migration was quantified by the colloidal gold migration assay. Matrix metalloproteinase (MMP)-2 secretion and activation were detected by gelatin zymography. Urokinase type plasminogen activator (uPA) activity was determined by a coupled colorimetric assay measuring the activity of generated plasmin. Student's t test and one-way ANOVA were used for statistical analysis. RESULTS: Using a VEGF neutralizing monoclonal antibody (mAb), we show that LPA-induced EOC invasion is dependent upon VEGF. Using the selective VEGF receptor (VEGFR)-2 inhibitor, SU1498, LPA-induced EOC invasion and migration were significantly inhibited in a concentration-dependent manner. In addition, SU1498 inhibits MMP-2 secretion and uPA activity in ovarian cancer DOV13 cells. At 5 and 20 microM, SU1498 almost completely inhibited the activity of MMP-2 and uPA. SU1498 also decreases the LPA-induced increase of uPA activity in DOV13 cells. CONCLUSIONS: Our results show that LPA-induced EOC invasion is at least partially mediated by VEGF. Further, the VEGFR-2-mediated signaling transduction pathway may be involved in LPA-induced EOC invasion and migration by regulating the secretion and activation of MMP-2 and uPA.