LEISHMANIA LIPOPHOSPHOGLYCAN REDUCES MONOCYTE TRANSENDOTHELIAL MIGRATION - MODULATION OF CELL-ADHESION MOLECULES, INTERCELLULAR JUNCTIONAL PROTEINS, AND CHEMOATTRACTANTS

We previously identified the structural requirement for the inhibitory activity of Leishmania lipophosphoglycan (LPG) to block endothelial a dhesion to monocytes, Here we showed that LPG reduces transendothelial migration of monocytes, LPG pretreatment of endothelial cells (2 mu M , 1 h) reduced monocyte migration across endothelial cells activated b y bacterial endotoxin (LPS) or IL-1 beta (60 and 46%, respectively). A fragment of LPG (i.e., repeating phosphodisaccharide (consisting of g alactosyl-mannose)) and LPG coincubated with LPG-neutralizing mAb lack s inhibitory activity on monocyte migration. Pretreatment of monocytes with LPG (2 mu M, 1 h) also did not affect monocyte migration through control or LPS-activated endothelial cells, FAGS analysis reveals tha t LPG treatment blocked the LPS-mediated expression of E-selectin, int ercellular adhesion molecule-1, and vascular cell adhesion molecule-1 on endothelial cells and monocyte adhesion without altering the integr ity of the endothelial monolayer, LPG (2 mu M, 1 h) alone was capable of altering the expression and distribution of two junctional adhesion molecules, CD31 and vascular endothelium cadherin, as well as reversi ng the effects of LPS on these proteins, The induction of endothelial cells by LPS to transcribe and release monocyte chemoattractant protei n-1 (MCP-1) was significantly reduced by LPG (40-65%), LPG treatment o f nonactivated endothelial cells also suppressed by 55 to 75% the mono cyte migration triggered by a MCP-1 chemoattractant gradient, and coin cubation of LPG with neutralizing mAb abrogated the inhibitory activit y. Together, these data point to a novel anti-inflammatory function of LPG in reducing monocyte migration across endothelial cells via a mec hanism of inhibition of endothelial expression of cell adhesion molecu les, modulation of intercellular junctional proteins, and synthesis of MCP-1.