IFN-γ Inhibits Activation-Induced Expression of E- and P-Selectin on Endothelial Cells

Abstract

E- and P-selectin are cell surface lectins that mediate leukocyte-endothelial cell adhesion and thereby participate in neutrophil recruitment into inflammatory sites. E-selectin can be induced on endothelial cells by various activators, including TNF-α, IL-1β, and PMA. Induction of E-selectin is blocked by pretreatment of endothelial cells with IL-4 or TGF-β, both of which have antiinflammatory properties in vivo. In addition to its well-known proinflammatory activities, IFN-γ also has antiinflammatory effects in vivo, one of which is inhibition of neutrophil recruitment. To determine whether IFN-γ inhibits neutrophil recruitment by inhibiting adhesion molecule expression, the effect of IFN-γ on activation-induced cell adhesion molecule expression by cultured HUVEC was evaluated. Pretreatment of endothelial cells with IFN-γ for 24 to 72 h before 6- to 24-h activation with IL-1β, TNF-α, or PMA resulted in significantly reduced levels of cell surface E-selectin, although levels of ICAM-1 and VCAM-1 were the same or increased. The reduction of cell surface E-selectin levels under these conditions was reflected in reduced levels of E-selectin mRNA, indicating an effect at the transcription level or RNA stability. Interestingly, the increase of cell surface P-selectin expression due to IL-4 treatment of HUVEC was also inhibited by IFN-γ, while constitutive levels of P-selectin were not. These results suggest that the inhibition of neutrophil recruitment by IFN-γ in vivo may be due, in part, to the ability of IFN-γ to inhibit E- and P-selectin up-regulation. Furthermore, these findings emphasize the process of leukocyte recruitment as an important step through which IFN-γ can direct the character of inflammatory reactions.