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  See comment in PubMed Commons belowRheumatology (Oxford). 2009 Jan;48(1):39-44. doi: 10.1093/rheumatology/ken412. Epub 2008 Nov 23.Lactoferrin is a survival factor for neutrophils in rheumatoid synovial fluid.Wong SH1, Francis N, Chahal H, Raza K, Salmon M, Scheel-Toellner D, Lord JM.Author information1Rheumatology Research Group, MRC Centre for Immune Regulation, Institute of Biomedical Research, Birmingham University, Birmingham, UK.AbstractOBJECTIVES: Lactoferrin is an iron-binding protein that is released from activated neutrophils at sites of inflammation and has anti-microbial as well as anti-inflammatory properties. This study set out to determine whether lactoferrin can delay neutrophil apoptosis and could act as a survival factor for neutrophils in SF.METHODS: Human peripheral blood and SF neutrophils were incubated with iron-free lactoferrin and apoptosis determined after 9 h. SF from patients with RA was added to isolated neutrophils, with or without immunodepletion of lactoferrin, and effects on neutrophil apoptosis determined. Levels of lactoferrin in SF were assessed and related to disease duration and markers of disease activity.RESULTS: Iron-free lactoferrin significantly delayed apoptosis of peripheral blood neutrophils, in a concentration-dependent manner after 9 h in culture (P < 0.04). Lactoferrin could also delay apoptosis of neutrophils isolated from SF of patients with RA. SF from patients with established RA delayed apoptosis of peripheral blood neutrophils and this effect was significantly reduced by depletion of lactoferrin (P < 0.03). Lactoferrin levels in SF from patients with established RA did not correlate with disease severity, but did correlate with markers of inflammation (CRP) and with the presence of RF. SF from patients with arthritis of <12 weeks duration did not contain significant levels of lactoferrin.CONCLUSION: Lactoferrin contributes to extended neutrophil survival in the rheumatoid joint in the established phase of RA but not in very early arthritis.PMID: 19029133 [PubMed - indexed for MEDLINE] PMCID: PMC2639483 Free PMC ArticleShareImages from this publication.See all images (5)Free textF ig . 1.Lactoferrin levels in RA SF. Lactoferrin concentrations were measured by ELISA in SFs from patients with RA of >2 yrs (n = 26) (•) or <3 months (♦) duration (n = 10) and in matched sera from 11 of the patients with established RA (▪). The median value is indicated by a bar.Lactoferrin is a survival factor for neutrophils in rheumatoid synovial fluidRheumatology (Oxford). 2009 January;48(1):39-44.F ig . 2.Effect of lactoferrin on neutrophil apoptosis and function. (A) Peripheral blood neutrophils were incubated with medium alone or with medium containing iron-free lactoferrin at the concentrations shown and apoptosis measured by loss of DiOC6 staining after 9 h in culture. All incubations also contained 10 μg/ml polymyxin B. Data are mean ± s.d. (n = 5) and *P < 0.04, **P < 0.02. (B) Neutrophils were incubated with 100 μg/ml lactoferrin (LTF) for 20 h prior to stimulation with fMLP and measurement of superoxide generation. Data are expressed as mean ± s.d. of the area under the curve (AUC) per 106 viable cells (n = 3). *P < 0.01. (C) Neutrophils isolated from RA synovial fluid were incubated with medium alone, 50 ng/ml GM-CSF or 100 μg/ml lactoferrin. Apoptosis was measured by active caspase 3 staining after 9 h in culture. Data are mean ± s.d. (n = 3) and *P < 0.05. All data were analysed by Student's t-test.Lactoferrin is a survival factor for neutrophils in rheumatoid synovial fluidRheumatology (Oxford). 2009 January;48(1):39-44.F ig . 3.Comparison of lactoferrin effects with known neutrophil survival factors. Peripheral blood neutrophils were incubated with medium alone (control), 100 ng/ml LPS, 800 IU/ml IFN-β, 50 ng/ml GM-CSF, 100 μg/ml lactoferrin (LTF) and apoptosis measured by differential staining and nuclear morphology after 9 h in culture. Data are mean ± s.d. (n = 5) and were analysed by ANOVA followed by Dunnett's comparison with control. *P < 0.05, **P < 0.01.Lactoferrin is a survival factor for neutrophils in rheumatoid synovial fluidRheumatology (Oxford). 2009 January;48(1):39-44.F ig . 4.The anti-apoptotic effect of synovial fluid is reduced by depletion of lactoferrin. Peripheral blood neutrophils were incubated with medium alone (control), or with synovial fluid from seven different RA patients which had been immunodepleted for lactoferrin (LTF) using an anti-lactoferrin monoclonal antibody (LTF) or mock-depleted using an isotype control immunoglobulin (Mock). Apoptosis was measured by active caspase 3 staining after 20 h in culture. Control and immunodepleted data were compared using a paired Student's t-test and *P < 0.03.Lactoferrin is a survival factor for neutrophils in rheumatoid synovial fluidRheumatology (Oxford). 2009 January;48(1):39-44.F ig . 5.Lactoferrin levels correlate with serum CRP and RF status. Lactoferrin levels were measured in synovial fluid of 24 patients with RA and correlated with (A) age, (B) disease duration, (C) serum ESR, (D) presence of joint erosion, (E) serum CRP and (F) seropositivity for RF. Data were analysed by Spearman's correlation.Lactoferrin is a survival factor for neutrophils in rheumatoid synovial fluidRheumatology (Oxford). 2009 January;48(1):39-44.Publication Types, MeSH Terms, Substances, Grant SupportPublication TypesResearch Support, Non-U.S. Gov'tMeSH TermsApoptosis/drug effectsArthritis, Rheumatoid/bloodArthritis, Rheumatoid/metabolismArthritis, Rheumatoid/pathology*Biological Markers/bloodC-Reactive Protein/analysisCell Survival/drug effectsCells, CulturedCytokines/pharmacologyHumansLactoferrin/analysisLactoferrin/pharmacology*Neutrophils/drug effects*Rheumatoid Factor/bloodSynovial Fluid/cytologySynovial Fluid/drug effects*SubstancesBiological MarkersCytokinesC-Reactive ProteinRheumatoid FactorLactoferrinGrant Support16390/Arthritis Research UK/United KingdomArthritis Research UK/United KingdomMedical Research Council/United KingdomLinkOut - more resourcesFull Text SourcesHighWireEBSCOEurope PubMed CentralOvid Technologies, Inc.PubMed CentralPubMed Central CanadaOther Literature SourcesLabome Researcher Resource - ExactAntigen/LabomeAccess more work from the authors - ResearchGateMedicalRheumatoid Arthritis - MedlinePlus Health InformationPubMed Commons home