Pantropical spotted dolphins are apex predators and have a long lifespan, which makes them susceptible to chemical pollutants such as polybrominated diphenyl ethers (PBDEs), which are associated with immunotoxicity in wildlife. However, the effects of PBDEs and their mechanism of immunotoxicity in dolphins is largely unknown. Previously, we established fibroblast cell lines obtained from pantropical spotted dolphins (PSD-LWHT) as an in vitro model for assessing the toxicological implications of chemical pollutants in dolphins. In this study, we used the novel immortalized fibroblast cell line to explore the potential immune stimulation effect of PBDEs via prostaglandins signaling pathways to better understand the immunotoxicity pathway of PBDEs in dolphins. BDE-47, -100, and −209 exposure generally resulted in an increase in inflammatory cytokine expression, PGE2 levels, and COX-2 gene expression but BDE-209 resulted in a suppression in IL-10 production. Both protein and mRNA expression of COX-2 and PTGES increased significantly following exposure to the PBDEs. The results suggested BDE-100 and -209 increased prostaglandin E2 (PGE2) production via increased expression of COX-2 and PTGES expression. Only BDE-100 increased expression level of the prostaglandin E2 receptor EP4 while BDE-47 and BDE-209 decreased its expression. This probably explained why suppressive effect on the expression level of anti-inflammatory cytokines were only found in exposure with BDE-47 and BDE-209 rather than BDE-100. The results showed that PBDEs stimulate innate immune response by triggering PGE2-EPs-cAMP-cytokines signaling.