This suggests that LECs exhibit differential responses to individual parasite stages or products. Furthermore, given that ES products contain products from both adult worms as well as microfilariae, and there was not an increase in cytokine production by LECs in response to ES products, these data also demonstrate a differential response between microfilarial ES products and microfilarial crude worm extract. Taken together, these data suggest that EC proliferation under these culture conditions does not result from direct exposure to adult female worm and microfilariae ES products; however, EC proliferation may require unidentified culture conditions, other parasite stages or involve other factors, such as accessory host cells or host-derived products. It should be noted that subsequent experiments in our lab revealed that filarial ES products stimulated human peripheral blood mononuclear cells, and specifically monocytes, to produce lymphangiogenic mediators arguing that the lack of measurable effects on LECs in response to worm ES products is not a result of protein concentration. Lymphangiogenic mediators produced by PBMCs in response to stimulation with filarial ES products were able to alter the behavior of LECs in vitro and in vivo as measured by tubule formation suggesting that LECs are indirectly activated by filarial ES products through the production of lymphangiogenic mediators from PBMCs. The involvement of host-derived products mediating lymphangiectasia is supported by the observation that serum from infected individuals can induce LEC proliferation. Even though we did not identify a reproducible activation event induced by worm ES, we did demonstrate robust responses of LECs to the positive controls, TNFa and LPS, in multiple assays. Here, we report that both TNFa and LPS stimulate LECs to activate cell signaling events, up-regulate cell surface adhesion molecules and induce growth factor and cytokine production. In conclusion, we were not able to demonstrate a direct activation of LECs by filarial ES products. The lack of evidence for a direct activation event may be explained by the limitations of an in vitro culture model system. Given the longevity of filarial infections, worms can exist in LVs for years where they release soluble factors that may gradually alter the lymphatic endothelium. In our in vitro cultures, we only carried out the LECstimulations with ES products for 72 hours; this may not be enough time to recreate the effects seen in infected vessels. The negative results may also suggest that a more complicated network is established between the parasite and the host and the LECs may be indirectly activated through a host accessory cell or its mediators.