Forsberg Maria, Druid Pia, Zheng Limin, Stendahl Olle, Särndahl Eva
Department of Cell Biology, Faculty of Health Sciences, Linköping University, Sweden.
J Leukoc Biol. 2003 Oct;74(4):611-9. doi: 10.1189/jlb.1102525. Epub 2003 Jul 1.
Phagocytosis is a complex process engaging a concerted action of signal-transduction cascades that leads to ingestion, subsequent phagolysosome fusion, and oxidative activation. We have previously shown that in human neutrophils, C3bi-mediated phagocytosis elicits a significant oxidative response, suggesting that activation of the small GTPase Rac is involved in this process. This is contradictory to macrophages, where only Fc receptor for immunoglobulin G (FcgammaR)-mediated activation is Rac-dependent. The present study shows that engagement of the complement receptor 3 (CR3) and FcgammaR and CR3- and FcgammaR-mediated phagocytosis activates Rac, as well as Cdc42. Furthermore, following receptor-engagement of the CR3 or FcgammaRs, a downstream target of these small GTPases, p21-activated kinase, becomes phosphorylated, and Rac2 is translocated to the membrane fraction. Using the methyltransferase inhibitors N-acetyl-S-farnesyl-L-cysteine and N-acetyl-S-geranylgeranyl-L-cysteine, we found that the phagocytic uptake of bacteria was not Rac2- or Cdc42-dependent, whereas the oxidative activation was decreased. In conclusion, our results indicate that in neutrophils, Rac2 and Cdc42 are involved in FcR- and CR3-induced activation and for properly functioning signal transduction involved in the generation of oxygen radicals.
吞噬作用是一个复杂的过程，涉及信号转导级联的协同作用，导致摄取、随后的吞噬溶酶体融合和氧化激活。我们之前已经表明，在人类中性粒细胞中，C3bi介导的吞噬作用会引发显著的氧化反应，这表明小GTP酶Rac的激活参与了这一过程。这与巨噬细胞相反，在巨噬细胞中，只有免疫球蛋白G的Fc受体（FcγR）介导的激活是Rac依赖性的。本研究表明，补体受体3（CR3）和FcγR的结合以及CR3和FcγR介导的吞噬作用会激活Rac以及Cdc42。此外，在CR3或FcγRs的受体结合后，这些小GTP酶的下游靶点p21激活激酶会被磷酸化，并且Rac2会转移到膜部分。使用甲基转移酶抑制剂N-乙酰基-S-法尼基-L-半胱氨酸和N-乙酰基-S-香叶基香叶基-L-半胱氨酸，我们发现细菌的吞噬摄取不依赖于Rac2或Cdc42，而氧化激活则会降低。总之，我们的结果表明，在中性粒细胞中，Rac2和Cdc42参与FcR和CR3诱导的激活以及参与氧自由基生成的信号转导的正常功能。
