Melrose J, Tsurushita N, Liu G, Berg E L
Protein Design Labs, Mountain View, CA 94043, USA.
J Immunol. 1998 Sep 1;161(5):2457-64.
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.
E选择素和P选择素是细胞表面凝集素，它们介导白细胞与内皮细胞的黏附，从而参与中性粒细胞募集至炎症部位的过程。多种激活剂，包括肿瘤坏死因子-α、白细胞介素-1β和佛波酯，均可在内皮细胞上诱导E选择素的表达。用白细胞介素-4或转化生长因子-β预处理内皮细胞可阻断E选择素的诱导，这两种因子在体内均具有抗炎特性。除了其众所周知的促炎活性外，干扰素-γ在体内也具有抗炎作用，其中之一是抑制中性粒细胞募集。为了确定干扰素-γ是否通过抑制黏附分子表达来抑制中性粒细胞募集，评估了干扰素-γ对培养的人脐静脉内皮细胞（HUVEC）激活诱导的细胞黏附分子表达的影响。在用白细胞介素-1β、肿瘤坏死因子-α或佛波酯激活6至24小时之前，先用干扰素-γ预处理内皮细胞24至72小时，结果细胞表面E选择素水平显著降低，而细胞间黏附分子-1（ICAM-1）和血管细胞黏附分子-1（VCAM-1）水平不变或升高。在这些条件下细胞表面E选择素水平的降低反映在E选择素mRNA水平的降低，表明在转录水平或RNA稳定性方面存在影响。有趣的是，干扰素-γ也抑制了白细胞介素-4处理人脐静脉内皮细胞导致的细胞表面P选择素表达的增加，而P选择素的组成性水平不受影响。这些结果表明，干扰素-γ在体内对中性粒细胞募集的抑制作用可能部分归因于其抑制E选择素和P选择素上调的能力。此外，这些发现强调了白细胞募集过程是干扰素-γ指导炎症反应特征的重要步骤。
