Background/Purpose: TNF is a key regulator of immune function and plays a pivotal role in inflammatory conditions such as rheumatoid arthritis. Human neutrophils express and release TNF, and are activated by it. Neutrophil responses to TNF are bimodal: low concentrations of TNF (~10 ng/mL) delay apoptosis but higher concentrations (>20 ng/mL) accelerate apoptosis. When neutrophils are activated to express TNF, complex regulatory mechanisms must control their response to both autocrine and paracrine signalling. This study investigated the mechanisms by which neutrophils respond to anti-apoptotic concentrations of TNF and control apoptosis delay. 

Methods: Human neutrophils were exposed to 10 ng/mL of TNF: apoptosis was determined by flow cytometry (annexin V/PI binding); gene expression was determined by analysis of mRNA levels, flow cytometery and western blotting. 

Results: Transcriptome analysis revealed that TNF signalling significantly increased mRNA levels for TNF, ICAM1, TNFAIP3, CD40, BFL1 plus several genes associated with NF-kB signalling. In contrast, mRNA levels of TNF receptor 1, TNF receptor 2, FADD, Bax and Caspase 8 were all significantly down-regulated. Many of these changes in mRNA levels were paralleled by changes in protein levels. These data indicate that neutrophils contribute to TNF-mediated signalling pathways via activated secretion of this cytokine. In parallel, they up-regulate genes that delay apoptosis (e.g. BFL1) but down-regulate expression of pro-apoptotic genes such as Bax and FADD. 

Conclusion: These data shed important new insights into understanding the function of neutrophils in inflammation and inflammatory diseases; neutrophils contribute to TNF-mediated inflammation and in doing so become more resistant to apoptosis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-effects-of-tnf-stimulation-on-control-of-apoptosis-in-neutrophils/