title: Lactoferrin inhibits neutrophil apoptosis via blockade of proximal apoptotic signaling events.
abstract: 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.
authors.affiliation: MRC Centre for Immune Regulation, Institute of Biomedical Research, Birmingham University, Birmingham B15 2TT, UK.
authors.forename: Nigel
authors.initials: N
authors.lastname: Francis
authors.forename: See Heng
authors.initials: SH
authors.lastname: Wong
authors.forename: Peter
authors.initials: P
authors.lastname: Hampson
authors.forename: Keqing
authors.initials: K
authors.lastname: Wang
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Young
authors.forename: Hans Peter
authors.initials: HP
authors.lastname: Deigner
authors.forename: Michael
authors.initials: M
authors.lastname: Salmon
authors.forename: Dagmar
authors.initials: D
authors.lastname: Scheel-Toellner
authors.forename: Janet M
authors.initials: JM
authors.lastname: Lord
mesh_terms: D001059:Apoproteins / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002518:Ceramides / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007501:Iron / Q000378:metabolism; D007781:Lactoferrin / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism
chemical_list: D001059:Apoproteins; D002518:Ceramides; C039223:apolactoferrin; D007501:Iron; D013108:Sphingomyelin Phosphodiesterase; D007781:Lactoferrin