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Blood, 15 August 2005, Vol. 106, No. 4, pp. 1432-1440.
Prepublished online as a Blood First Edition Paper on May 5, 2005; DOI 10.1182/blood-2005-03-0944.
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Submitted March 8, 2005
Accepted April 19, 2005
Sequential activation of Class IB and Class IA PI3Ks is important for the primed respiratory burst of human but not murine neutrophils
Alison M Condliffe, Keith Davidson, Karen E Anderson, Chris D Ellson, Tom Crabbe, Klaus Okkenhaug, Bart Vanhaesebroeck, Martin Turner, Louise Webb, Matthias P Wymann, Emilio Hirsch, Thomas Ruckle, Montserrat Camps, Christian Rommel, Shaun P Jackson, Edwin R Chilvers, Len R Stephens, and Phillip T Hawkins*
The Inositide Laboratory, Babraham Institute, Babraham Research Campus, Cambridge, United Kingdom
Celltech R&D Ltd, Slough, Berkshire, United Kingdom
Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Babraham Research Campus, Cambridge, United Kingdom
Ludwig Institute for Cancer Research and Dept. Biochemistry and Molecular Biology, London, United Kingdom
Centre of Biomedicine, Dept. Clinical & Biological Science, University of Basel, Basel, Switzerland
Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy
Serono Pharmaceutical Research Institute, Geneva, Switzerland
Australian Centre for Blood Diseases, Monash University, Victoria, Australia
Respiratory Medicine Division, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Cambridge, United Kingdom
* Corresponding author; email: phillip.hawkins{at}bbsrc.ac.uk.
It is well established that pre-exposure of human neutrophils to pro-inflammatory cytokines markedly augments production of reactive oxygen species (ROS) to subsequent stimuli. This priming event is thought to be critical for localising ROS to the vicinity of the inflammation, maximising their role in the resolution of the inflammation and minimising damage to surrounding tissue. We have used a new generation of isoform-selective phosphoinositide 3-kinase (PI3K) inhibitors to show that ROS production under these circumstances is regulated by temporal control of Class I PI3K activity. Stimulation of TNF- primed human neutrophils with fMLP results in biphasic activation of PI3K; the first phase is largely dependent on PI3K- and the second phase is largely dependent on PI3K- . The second phase of PI3K activation requires the first phase and it is this second phase which is augmented by TNF- priming and which regulates parallel activation of ROS production. Surprisingly, although TNF- primed mouse bone-marrow derived neutrophils exhibit superficially similar patterns of PI3K activation and ROS production in response to fMLP, these responses are substantially lower and largely dependent on PI3K- alone. These results start to define which PI3K isoforms are responsible for modulating neutrophil responsiveness to infection and inflammation.
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