Francis Nigel, Wong See Heng, Hampson Peter, Wang Keqing, Young Stephen P, Deigner Hans Peter, Salmon Michael, Scheel-Toellner Dagmar, Lord Janet M
MRC Centre for Immune Regulation, Institute of Biomedical Research, Birmingham University, Birmingham B15 2TT, UK.
Biochim Biophys Acta. 2011 Oct;1813(10):1822-6. doi: 10.1016/j.bbamcr.2011.07.004. Epub 2011 Jul 19.
Neutrophils are the most abundant leukocyte and have a short lifespan, dying by apoptosis approximately five days after leaving the bone marrow. Their apoptosis can be delayed at sites of inflammation to extend their functional lifespan, but inappropriate inhibition of apoptosis contributes to chronic inflammatory disease. Levels of the physiological iron chelator lactoferrin are raised at sites of inflammation and we have shown previously that iron-unsaturated lactoferrin inhibited human neutrophil apoptosis, but the mechanisms involved were not determined. Here we report that the anti-apoptotic effect of lactoferrin is dependent upon its iron saturation status as iron-saturated lactoferrin did not affect neutrophil apoptosis. We also show that the effect of lactoferrin is mediated at an early stage in apoptosis as it inhibited activation of sphingomyelinase, generation of ceramide, activation of caspase 8 and Bax and cleavage of Bid. Lactoferrin did not inhibit apoptosis induced by exogenous ceramide, supporting the proposal that it acts upstream of ceramide generation. We therefore conclude that raised lactoferrin levels are likely to contribute to chronic inflammation by delaying neutrophil apoptosis and that this is achieved by inhibiting proximal apoptotic signaling events.
中性粒细胞是最丰富的白细胞，寿命较短，离开骨髓后约五天通过凋亡死亡。它们的凋亡在炎症部位可被延迟，以延长其功能寿命，但凋亡的不适当抑制会导致慢性炎症性疾病。生理性铁螯合剂乳铁蛋白的水平在炎症部位升高，我们之前已经表明，铁不饱和乳铁蛋白可抑制人类中性粒细胞凋亡，但其中涉及的机制尚未确定。在此我们报告，乳铁蛋白的抗凋亡作用取决于其铁饱和状态，因为铁饱和乳铁蛋白不影响中性粒细胞凋亡。我们还表明，乳铁蛋白的作用在凋亡早期介导，因为它抑制了鞘磷脂酶的激活、神经酰胺的生成、半胱天冬酶8和Bax的激活以及Bid的切割。乳铁蛋白不抑制外源性神经酰胺诱导的凋亡，支持了其作用于神经酰胺生成上游的观点。因此，我们得出结论，乳铁蛋白水平升高可能通过延迟中性粒细胞凋亡导致慢性炎症，并且这是通过抑制近端凋亡信号事件实现的。
