Granulocyte apoptosis has been proposed as a fundamental, injury-limiting granulocyte-clearance mechanism. As such, inhibition of this process may prevent the resolution of inflammation. Our previous studies have shown that TNFα (tumour necrosis factor-α) has a bi-modal influence on the rate of constitutive neutrophil apoptosis in vitro, causing early acceleration and late inhibition of this process. The pro-apoptotic effect is uniquely TNFR1 (TNF receptor 1) and TNFR2-dependent and the latter survival process is mediated via phosphoinositide 3-kinase and NF-κB (nuclear factor-κB) activation. In the present study, we show that, in contrast with GM-CSF (granulocyte/macrophage colony-stimulating factor), the delayed addition (i.e. at 6 h) of TNFα increases its survival effect despite substantial loss of neutrophil TNFR1 and TNFR2 at that time. This paradox was resolved using PBMC (peripheral blood mononuclear cell)-deplete and 5% PBMC-replete neutrophil cultures, where the enhanced survival effect observed after delayed TNFα addition was shown to be PBMC-dependent. TNFR2-blocking antibodies had no effect on the late survival effect of TNFα, implying a TNFR1-dependent process. Finally, I-κBα (inhibitory κB-α) and NF-κB time-course studies demonstrated that the survival effects of both GM-CSF and TNFα could be explained by maintenance of functional NF-κB.
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Conference Article|
June 01 2004
Characterization of the survival effect of tumour necrosis factor-α in human neutrophils
S.R. Walmsley;
S.R. Walmsley
*Respiratory Medicine Division, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Hills Road, Cambridge CB2 2QQ, U.K.
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A.S. Cowburn;
A.S. Cowburn
*Respiratory Medicine Division, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Hills Road, Cambridge CB2 2QQ, U.K.
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A. Sobolewski;
A. Sobolewski
*Respiratory Medicine Division, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Hills Road, Cambridge CB2 2QQ, U.K.
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J. Murray;
J. Murray
†Department of Respiratory Medicine, University of Edinburgh, Teviot Place, Edinburgh, U.K.
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N. Farahi;
N. Farahi
*Respiratory Medicine Division, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Hills Road, Cambridge CB2 2QQ, U.K.
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I. Sabroe;
I. Sabroe
‡Academic Unit of Respiratory Medicine, Division of Genomic Medicine, University of Sheffield, The Royal Hallamshire Hospital, Sheffield, U.K.
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E.R. Chilvers
E.R. Chilvers
1
*Respiratory Medicine Division, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Hills Road, Cambridge CB2 2QQ, U.K.
1To whom correspondence should be addressed (email erc24@cam.ac.uk).
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Publisher: Portland Press Ltd
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2004 Biochemical Society
2004
Biochem Soc Trans (2004) 32 (3): 456–460.
Citation
S.R. Walmsley, A.S. Cowburn, A. Sobolewski, J. Murray, N. Farahi, I. Sabroe, E.R. Chilvers; Characterization of the survival effect of tumour necrosis factor-α in human neutrophils. Biochem Soc Trans 1 June 2004; 32 (3): 456–460. doi: https://doi.org/10.1042/bst0320456
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