IFN-gamma inhibits activation-induced expression of E- and P-selectin on endothelial cells.
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-alpha, IL-1beta, and PMA. Induction of E-selectin is blocked by pretreatment of endothelial cells with IL-4 or TGF-beta, both of which have antiinflammatory properties in vivo. In addition to its well-known proinflammatory activities, IFN-gamma also has antiinflammatory effects in vivo, one of which is inhibition of neutrophil recruitment. To determine whether IFN-gamma inhibits neutrophil recruitment by inhibiting adhesion molecule expression, the effect of IFN-gamma on activation-induced cell adhesion molecule expression by cultured HUVEC was evaluated. Pretreatment of endothelial cells with IFN-gamma for 24 to 72 h before 6- to 24-h activation with IL-1beta, TNF-alpha, 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-gamma, while constitutive levels of P-selectin were not. These results suggest that the inhibition of neutrophil recruitment by IFN-gamma in vivo may be due, in part, to the ability of IFN-gamma to inhibit E- and P-selectin up-regulation. Furthermore, these findings emphasize the process of leukocyte recruitment as an important step through which IFN-gamma can direct the character of inflammatory reactions.
Melrose
J
J
Protein Design Labs, Mountain View, CA 94043, USA.
Tsurushita
N
N
Liu
G
G
Berg
E L
EL
D002448:Cell Adhesion / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D019040:E-Selectin / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D005434:Flow Cytometry; D018922:HL-60 Cells; D006684:HLA-DR Antigens / Q000096:biosynthesis; D006801:Humans; D007106:Immune Sera / Q000494:pharmacology; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology*; D009500:Neutralization Tests; D018375:Neutrophil Activation / Q000187:drug effects* / Q000276:immunology; D019007:P-Selectin / Q000096:biosynthesis* / Q000187:drug effects; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D014471:Umbilical Veins
D019040:E-Selectin; D006684:HLA-DR Antigens; D007106:Immune Sera; D019007:P-Selectin; D012333:RNA, Messenger; D007371:Interferon-gamma