Ligands of toll-like receptors 2/4 differentially alter markers of inflammation, adhesion and angiogenesis by monocytes from women with pre-eclampsia in co-culture with endothelial cells

Pre-eclampsia (PE) is characterized by an exaggerated systemic inflammatory response and generalized endothelial dysfunction. We have recently demonstrated that fibrinogen, an endogenous ligand of Toll-like receptor (TLR) 4, activates monocytes from women with pre-eclampsia (Al-ofi et al., 2014). Using an experimental co-culture model of primary human monocytes (derived from 9 women with PE (GA = 33.18 ± 5.8) and 9 normotensive pregnant women, NP (GA = 33.15 ± 4.0)) and human umbilical venous endothelial cells (HUVECs), we compared the effects of fibrinogen and lipopolysaccharide (LPS, bacterial ligand to TLR4) on the expression levels of inflammatory cytokines (IL-6 and IL-1β), chemokines (IL-8 and MCP-1), and anti-angiogenic factor (soluble fms-like tyrosine kinase-1,sFLT-1), as well as the soluble vascular cell adhesion molecule-1 (sVCAM-1). Cytokines, VEGF and sVCAM-1 were measured in the supernatant media by cytometric array. The levels of sFLT-1 were measured by ELISA. Fibrinogen induced greater expression levels of IL-1β and VCAM-1 from PE HUVEC-monocyte co-culture than from NP HUVEC-monocyte co-culture (P < 0.05), similar to the effects of LPS. In contrast, unlike LPS, fibrinogen suppressed IL-6, IL-8, MCP-1 and sFLT-1 production by co-cultures that included PE monocytes compared to those with NP monocytes (P < 0.05). In conclusion, fibrinogen promotes monocyte-endothelial cell adhesion and angiogenesis and suppresses the expression of some inflammatory markers in pre-eclampsia. Although the physiological implications of these intriguing observations are unclear our findings suggest that fibrinogen contributes to the regulation of cell adhesion, angiogenesis and inflammation by mechanisms not wholly dependent on TLR4 stimulation.