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Lactoferrin inhibits neutrophil apoptosis via blockade of proximal apoptotic signaling events

Francis, Nigel ORCID:, Wong, See Heng, Hampson, Peter, Wang, Keqing, Young, Stephen P., Deigner, Hans Peter, Salmon, Michael, Scheel-Toellner, Dagmar and Lord, Janet M. 2011. Lactoferrin inhibits neutrophil apoptosis via blockade of proximal apoptotic signaling events. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1813 (10) , pp. 1822-1826. 10.1016/j.bbamcr.2011.07.004

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: Elsevier
ISSN: 0167-4889
Date of First Compliant Deposit: 5 October 2021
Date of Acceptance: 8 July 2011
Last Modified: 23 May 2023 14:37

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