ENDOTHELIAL-CELLS ARE ACTIVATED BY CYTOKINE TREATMENT TO KILL AN INTRAVASCULAR PARASITE, SCHISTOSOMA-MANSONI, THROUGH THE PRODUCTION OF NITRIC-OXIDE

Like many pathogens that undergo an intravascular stage of development , larvae of the helminth parasite Schistosoma mansoni migrate through the blood vessels, where they are in close contact with endothelial ce lls. In vitro exposure of murine endothelial cells to various cytokine s (interferon gamma, tumor necrosis factor alpha, and interleukin 1alp ha or 1beta) resulted in their activation to kill schistosomula throug h an arginine-dependent mechanism involving production of nitric oxide (NO). Cytokine-treated endothelial cells showed increased expression of mRNA for the inducible form of the NO synthase, and both NO product ion and larval killing were suppressed by treatment with competitive i nhibitors. The effector function of cytokine-treated endothelial cells was similar to that of activated inflammatory tissue macrophages, alt hough activation appeared to be differentially regulated in these two cell types. Activated endothelial cells killed older (18-day) forms of the parasite, such as those currently thought to be a primary target of immune elimination in the lungs of mice previously vaccinated with radiation-attenuated cercariae, as well as newly transformed larvae. I n C57BL/6 mice, which become resistant to S. mansoni infection as a re sult of vaccination with irradiated cercariae, endothelial cell morpho logy characteristic of activation was observed in the lung by 1-2 week s after challenge infection. Similar endothelial cell changes were abs ent in P-strain mice, which do not become resistant as a result of vac cination. Together, these observations indicate that endothelial cells , not traditionally considered to be part of the immune system, may pl ay an important role in immunity to S. mansoni and, by means of NO-dep endent killing, could serve as effectors of resistance to other intrav ascular pathogens.