Regulation of biodefense system by neutrophil apoptosis

在稳态条件下，中性粒细胞的大量日常生产通过它们在组织中的消失和凋亡来平衡，而不会引起炎症反应。正常情况下，中性粒细胞消失在肺、口腔和胃肠道中，它们可能从粘膜表面消失或死亡，被巨噬细胞隔离。在牙周组织中浸润和活化的中性粒细胞释放酶、氧自由基、细胞因子和炎症介质，它们的持续积累与组织基质或器官功能的破坏有关，导致牙周疾病的恶化。因此，通过凋亡消除中性粒细胞确实是停止炎症的潜在损伤限制细胞处置机制。在本研究中，我们研究了外周和口腔中性粒细胞凋亡的机制。外周中性粒细胞的细胞核与钙和镁孵育后，核体间DNA片段增多，而口服中性粒细胞则没有。放线菌素D和tnf - α诱导外周中性粒细胞凋亡，显示核体间DNA断裂，但口服中性粒细胞对刺激具有抗性。当外周中性粒细胞被TPA或FMLP处理后，再培养一段时间，它们经历了DNA断裂的凋亡，并且不像口服中性粒细胞那样对凋亡不敏感。从血管向口腔迁移过程中获得的其他信号可能参与了口腔中性粒细胞对细胞凋亡的抵抗。多种细胞内信号通路调节剂，包括蛋白激酶C和半胱天冬酶，已被证明参与中性粒细胞存活和凋亡的调节。然而，PKC抑制剂H-7和caspase抑制剂AcY VADcmK不影响外周中性粒细胞的DNA断裂。HL-60细胞分化为粒细胞后，在蛋白酶体抑制胸腺细胞凋亡的作用下发生凋亡。中性粒细胞的凋亡难以定量测定，因此应考虑凋亡特异性分子如Fas-FasL和Bcl-2来阐明中性粒细胞凋亡的机制。在牙周病变中，包括巨噬细胞、中性粒细胞和淋巴细胞在内的炎症细胞的凋亡受到不同机制的调控，从而调节牙周炎。少

Under steady-state conditions, the large daily production of neutrophils is balanced by their disappearance and apoptosis in the tissues without eliciting an inflammatory response. Normally, neutrophils disappear into the lung, oral cavity and gastrointestinal tract, where they may be lost from mucosal surfaces or die and become sequestered by macrophages. Infiltrated and activated neutrophils in periodontal tissues release enzymes, oxygen radicals, cytokines, and mediators of inflammation, and their persistent accumulation is associated with the destruction of tissue matrix or organ function, resulting in an exasperation of periodontal diseases. Thus, neutrophil elimination by apotosis is indeed a potentially injury-limiting cell disposal mechanism for the cessation of inflammation. In the present studies, we examined the mechanism of apoptosis of peripheral and oral neutrophils.When the nuclei from peripheral neutrophils were incubated with calcium and magnesium, internucleosomal DNA … More fragmentation was observed, but not in oral neutrophils. Peripheral neutrophil apoptosis was induced by actinomycin D and TNF-alpha, revealing internucleosomal DNA fragmentation, but oral neutrophils were resistant to the stimuli. When peripheral neutrophils were treated by TPA or FMLP which prime the cells, and cultured for an additional time, they underwent apoptosis with DNA fragmentation and did not become insensitive to apoptosis as oral neutrophils. Other signals which are aquired during migration to the oral cavity from the vessels may participate in the resistancy to apoptosis in oral neutrophils. A variety of modulators of intracellular signaling pathways, including protein kinase C and caspases, have been shown to participate in the regulation of neutrophil survival and apoptosis.However, H-7, an inhibitor of PKC,and AcY VADcmK,a caspase inhibitor, did not affect the DNA fragmentation in peripheral neutrophils.HL-60 cells which differentiate to granulocytes, underwent apoptosis by the inhibitor of proteasome which inhibited thymocytes apoptosis. It is difficult to measure neutrophil apoptosis quantitatively, therefor the apoptosis specific molecules such as Fas-FasL and Bcl-2 should be considered to elucidate the mechanism of neutrophil apoptosis.In the periodontal lesions, apoptosis of inflammatory cells including macrophages, neutrophils and lymphocytes is regulated by different mechanisms and modulates periodontitis. Less