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BJA Advance Access published online on November 19, 2004
British Journal of Anaesthesia, doi:10.1093/bja/aei021
© 2004 by The Board of Management and Trustees of the British Journal of Anaesthesia
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Accepted September 23, 2004

Laboratory Investigation

Release of tumour necrosis factor {alpha} (TNF{alpha}) by TNF{alpha} cleaving enzyme (TACE) in response to septic stimuli in vitro{dagger}

H. J. Robertshaw 1* and F. M. Brennan 2

1 Anaesthesia and Intensive Care Medicine, St George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK
2 Kennedy Institute of Rheumatology Division, Imperial College Faculty of Medicine, 1 Aspenlea Road, London W6 8LH, UK

* To whom correspondence should be addressed.
H. J. Robertshaw, E-mail: hroberts{at}sghms.ac.uk


  Abstract

Background. Tumour necrosis factor {alpha} (TNF{alpha}), in its soluble form (solTNF), has been well described as an important cytokine in inflammatory states including sepsis. The transmembrane precursor of solTNF, membrane-bound TNF{alpha} (memTNF), is cleaved by TNF{alpha} cleaving enzyme (TACE), the regulation of which is poorly understood. We hypothesized that the diversity of clinical features seen with sepsis caused by different organisms may be a result of differential regulation of TACE. Therefore, we measured these proteins in models of sepsis using flow cytometric methods that we have developed.

Methods. Surface protein expression of memTNF and TACE, and TACE catalytic activity were measured in human monocytes by flow cytometry following cell stimulation by lipopolysaccharide (LPS), zymosan (a yeast cell wall product) or heat-inactivated Neisseria meninigitidis.

Results. Unstimulated human monocytes express memTNF on the cell surface (mean fluorescence intensity, MFI 131) and this is down-regulated initially in response to LPS (MFI 57) but then recovers to exceed the resting protein expression (MFI 614). TACE protein is also present on the surface of resting cells (MFI 389) but is catalytically inactive until cell stimulation. Stimulation of monocytes with LPS, zymosan and Neisseria meningitidis produced different patterns of TACE activation with time.

Conclusions. The regulation of memTNF by TACE on monocytes is an important regulatory event in the pro-inflammatory cytokine cascade. As monocytes are important in the inflammatory cascade, we suggest that the control of memTNF and TACE activity on monocytes may play a role in the pathophysiology of sepsis.

Keywords: blood, monocytes; measurement techniques, flow cytometry; polypeptide, cytokines.

{dagger} Part of this paper has been presented in abstract form at the ARS meetings in Nottingham (November 2001) and Cardiff (July 2002).


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