Schistosoma mansoni schistosomula reduce E-selectin and VCAM-1 expression in TNF-alpha-stimulated lung microvascular endothelial cells by interferingwith the NF-kappa B pathway

The recruitment of immune cells into the lungs is a key step in protection against murine schistosomiasis. In this phenomenon, pulmonary (micro)vascul ar endothelial cells (EC) probably play a central role, by expressing speci fic adhesion molecules on their surface. Recently, we have shown that Schis tosoma mansoni schistosomula, the parasitic stage which resides in the lung s, could activate microvascular EC to acquire an anti-inflammatory phenotyp e. In the present study, we tested the hypothesis that schistosomula could also regulate the expression of adhesion molecules in vitro by human lung m icrovascular EC (HMVEC-I) in the present of the pro-inflammatory cytokine T NF-alpha. We found that lipophilic substance(s) present in the excretory/se cretory products from schistosomula selectively reduce the TNF-alpha-induce d synthesis of E-selectin and VCAM-1 mRNA and proteins without affecting IC AM-1. This inhibitory effect appears to be mediated by a cyclic AMP/protein kinase A (cAMP/PKA) pathway that probably interferes with the NF-kappa B p athway induced by TNF-alpha at the level of the E-selectin promoter, wherea s a cAMP-independent pathway appears to operate in VCAM-1 down-modulation. Finally, schistosomula also significantly reduce the VLA-4/VCAM-1-dependent adherence of leukocytes to TNF-alpha-stimulated HMVEC-I. We speculate that this mechanism could represent a new stratagem that parasites may use to e scape the immune system by controlling leukocyte recruitment to the lungs.