Inflammatory Cytokines Regulate VEGFR‐3/Flt‐4 Expression in Lymphatic Endothelial Cells

Lymphangiogenesis is recognized as an important event in inflammation/resolution. Lymphangiogenesis is known to be regulated by the VEGFR‐3/Flt‐4 receptor, which binds VEGF‐C and VEGF‐D. Changes in the expression of VEGFR‐3/Flt‐4 might have a considerable effect on ability of cells like lymphatic endothelial cell's (LECs) to respond to these growth factors. Currently, it is not known how inflammatory cytokines affect the expression of VEGFR‐3/Flt‐4. We investigated the effects of TNF‐α, IL‐1β, and IFN‐γ on VEGFR‐3/Flt‐4 expression in LECs in vitro. Our data suggest that IL‐1β downregulated VEGFR‐3/Flt‐4 expression, IFN‐γ upregulated VEGFR‐3/Flt‐4 expression, while TNF‐α had a minor effect. Compared to the controls without inflammatory cytokine stimulation, TNF‐α (20ng/ml) had no effect on VEGR‐3/Flt‐4 expression (89 ± 10 % of control, not sig.), however, IL‐1β (10ng/ml) appeared to downregulate VEGFR‐3/Flt‐4 expression (65 ± 12% of control, **p<0.01), while IFN‐γ (1000 U/ml) appeared to upregulate VEGFR‐3/Flt‐4 expression (157 ± 8.1 % of control, p<0.001). These data indicate that inflammatory cytokines produced by immune cells can regulate receptors involved in the control of lymphangiogenesis. Supported by NIH grant DK43785 and a grant‐in‐aid from the American Heart Association.