Forsberg M, Löfgren R, Zheng L, Stendahl O
Division of Medical Microbiology, Department of Health and Care, Faculty of Health Sciences, Linköping University, SE-581 85 Linköping, Sweden.
Immunology. 2001 Aug;103(4):465-72. doi: 10.1046/j.1365-2567.2001.01270.x.
CR3 and Fc gamma Rs are the main receptors involved in the phagocytic process leading to engulfment and killing of microbes by production of reactive oxygen intermediates (ROI) and degranulation. Various inflammatory mediators, such as tumour necrosis factor-alpha (TNF-alpha) and lipopolysaccharide (LPS), are known to prime neutrophils leading to increased bactericidal responses, but the underlying mechanism of priming has only been partially elucidated. The purpose of this study was to investigate how TNF-alpha primes neutrophils for subsequent stimuli via either CR3 or Fc gamma R. The receptors were specifically activated with pansorbins (protein-A-positive Staphylococcus aureus) coated with anti-CR3, anti-Fc gamma RIIa, or anti-Fc gamma RIIIb monoclonal antibody. Activation of neutrophils with these particles resulted in ROI production as measured by chemiluminescence. Anti-CR3 pansorbins induced the most prominent ROI production in neutrophils. TNF-alpha potentiated the CR3-mediated respiratory burst but had little effect on that mediated by Fc gamma Rs. The priming effect of TNF-alpha on CR3-mediated ROI production is associated with an increased activation of p38 MAPK as well as tyrosine phosphorylation of p72(syk). Pretreatment of neutrophils with the inhibitors for p38 MAPK and p72(syk) markedly suppressed the respiratory burst induced by CR3. Furthermore, TNF-alpha induced about a three-fold increase in the expression of CR3 in neutrophils, an effect which is blocked by the p38 MAPK inhibitor. Taken together, these results showed that TNF-alpha potentiates the CR3-mediated respiratory burst in neutrophils not only by triggering a p38 MAPK-dependent up-regulation of CD11b/CD18 but also by modulating the signalling pathways.
CR3和FcγR是参与吞噬过程的主要受体，该过程通过产生活性氧中间体（ROI）和脱颗粒导致微生物的吞噬和杀伤。已知多种炎症介质，如肿瘤坏死因子-α（TNF-α）和脂多糖（LPS），可使中性粒细胞致敏，导致杀菌反应增强，但致敏的潜在机制仅得到部分阐明。本研究的目的是探讨TNF-α如何通过CR3或FcγR使中性粒细胞对后续刺激致敏。用包被有抗CR3、抗FcγRIIa或抗FcγRIIIb单克隆抗体的泛吸附菌素（蛋白A阳性金黄色葡萄球菌）特异性激活这些受体。用这些颗粒激活中性粒细胞会导致通过化学发光法测定的ROI产生。抗CR3泛吸附菌素在中性粒细胞中诱导出最显著的ROI产生。TNF-α增强了CR3介导的呼吸爆发，但对FcγR介导的呼吸爆发影响很小。TNF-α对CR3介导的ROI产生的致敏作用与p38 MAPK的激活增加以及p72(syk)的酪氨酸磷酸化有关。用p38 MAPK和p72(syk)抑制剂预处理中性粒细胞可显著抑制CR3诱导的呼吸爆发。此外，TNF-α使中性粒细胞中CR3的表达增加约三倍，这一作用被p38 MAPK抑制剂阻断。综上所述，这些结果表明，TNF-α增强中性粒细胞中CR3介导的呼吸爆发，不仅是通过触发p38 MAPK依赖的CD11b/CD18上调，还通过调节信号通路来实现。
