Characterization of the survival effect of tumour necrosis factor-α in human neutrophils

Walmsley, S.R., Cowburn, A.S., Sobolewski, A., Murray, J., Farahi, N., Sabroe, I. and Chilvers, E. R. (2004) Characterization of the survival effect of tumour necrosis factor-α in human neutrophils. Biochemical Society Transactions, 32 (3). pp. 456-460. ISSN 0300-5127

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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.

Item Type: Article
Faculty \ School: Faculty of Science > School of Biological Sciences
Faculty of Science > School of Pharmacy
UEA Research Groups: Faculty of Science > Research Groups > Molecular and Tissue Pharmacology
Depositing User: Pure Connector
Date Deposited: 12 Oct 2016 15:00
Last Modified: 22 Oct 2022 01:44
DOI: 10.1042/bst0320456

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