Graham I L, Lefkowith J B, Anderson D C, Brown E J
Department of Pediatrics, Washington University Medical School, St. Louis, Missouri 63110.
J Cell Biol. 1993 Mar;120(6):1509-17. doi: 10.1083/jcb.120.6.1509.
The beta 2 integrins (LFA-1, Mac-1, and p150,95) are critical for many adhesive functions of leukocytes. Although the binding of the IgG-opsonized particles occurs normally in the absence of beta 2 integrins, phagocytosis of IgG-opsonized particles by activated neutrophils (PMN) requires these integrins. This observation suggests a role for beta 2 integrins in phagocytosis subsequent to particle binding. To investigate the mechanism of involvement of beta 2 integrins in IgG-mediated functions, we examined the role of beta 2 integrins in adhesion to immune complex (IC)-coated surfaces. Initial adhesion and spreading on IC-coated surfaces were equivalent in control and beta 2-deficient phagocytes. However, both genetically beta 2-deficient PMN and PMN treated with the anti-beta 2 mAb IB4 subsequently detached from the IC-coated surfaces. To determine whether biochemical consequences of IgG activation were also affected by beta 2 deficiency, LTB4 production in response to Fc receptor ligation was assessed. LTB4 production by beta 2-deficient PMN adherent to IC-coated surfaces was markedly decreased in comparison with control PMN. Importantly, LTB4 production by PMN stimulated with fluid phase heat-aggregated IgG also required the beta 2 integrins, showing that the defect was not a simple consequence of abnormal adhesion. In contrast, superoxide production by IC-adherent PMN was equivalent in control and beta 2-deficient PMN. The initial rises in intracytoplasmic [Ca2+]i in response to aggregated IgG also were unaffected by inhibition of beta 2 integrins. These data show that lack of beta 2 integrins does not inhibit all FcR-dependent signal transduction. Finally, LTB4 production by normal PMN adherent to ICs was inhibited by antibodies to FcRII, but not FcRIII, showing that FcRII ligation was required for this effect. Together these data identify a role for the beta 2 integrins in a signal transduction pathway leading to sustained adhesion and LTB4 production in response to IC. Since both beta 2 integrins and FcRII are required for these effects, the data further suggest cooperation between these receptors in generating PMN activation in response to IC stimulation.
β2整合素（淋巴细胞功能相关抗原-1、巨噬细胞抗原-1和p150,95）对白细胞的许多黏附功能至关重要。尽管在缺乏β2整合素的情况下，IgG调理颗粒的结合正常发生，但活化的中性粒细胞（PMN）对IgG调理颗粒的吞噬作用需要这些整合素。这一观察结果表明β2整合素在颗粒结合后的吞噬作用中发挥作用。为了研究β2整合素参与IgG介导功能的机制，我们研究了β2整合素在黏附于免疫复合物（IC）包被表面中的作用。对照吞噬细胞和β2缺陷吞噬细胞在IC包被表面的初始黏附和铺展情况相同。然而，基因敲除β2的PMN和用抗β2单克隆抗体IB4处理的PMN随后都从IC包被表面脱离。为了确定IgG激活的生化后果是否也受β2缺陷的影响，我们评估了对Fc受体连接的反应中白三烯B4（LTB4）的产生。与对照PMN相比，黏附于IC包被表面的β2缺陷PMN产生的LTB4明显减少。重要的是，液相热聚集IgG刺激PMN产生LTB4也需要β2整合素，表明该缺陷并非异常黏附的简单后果。相比之下，IC黏附的PMN产生超氧化物的情况在对照PMN和β2缺陷PMN中相同。对聚集IgG反应时胞质内[Ca2+]i的初始升高也不受β2整合素抑制的影响。这些数据表明，缺乏β2整合素并不抑制所有FcR依赖的信号转导。最后，正常PMN黏附于IC时产生LTB4受到抗FcRII抗体的抑制，但不受抗FcRIII抗体的抑制，表明这种效应需要FcRII连接。这些数据共同确定了β2整合素在导致对IC产生持续黏附和LTB4产生的信号转导途径中的作用。由于这些效应同时需要β2整合素和FcRII，数据进一步表明这些受体在响应IC刺激产生PMN激活方面存在协同作用。
