This book describes the role of the neutrophil in infection and inflammation and provides an up-to-date review of the biochemistry and physiology of these cells, highlighting the mechanisms by which they seek out and destroy pathogenic micro-organisms. The development of these cells during haematopoiesis is described and the mechanisms which lead to the production of reactive oxidants and the intracellular signal transduction systems which lead to the cell's activation are reviewed. The book also discusses recent discoveries concerning the role of cytokines in the regulation of neutrophil function together with the importance of the neutrophil as a generator of inflammatory cytokines. Finally there is a description of the biochemical defects that give rise to some of the neutrophil-associated human diseases.

Human neutrophils possess a very short half-life because they constitutively undergo apoptosis. Cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), and other agents can rescue neutrophils from apoptosis but the molecular mechanisms involved in this rescue are undefined. Here, we show by Western blotting that human neutrophils do not express Bcl-2 or Bcl-X but constitutively express Bax. However, cellular levels of these proteins are unaffected by agents which either accelerate or delay neutrophil apoptosis. In contrast, neutrophils express the antiapoptotic protein Mcl-1 and levels of this protein correlate with neutrophil survival. Thus, cellular levels of Mcl-1 decline as neutrophils undergo apoptosis and are enhanced by agents (eg, GM-CSF, interleukin-1β, sodium butyrate, and lipopolysaccharide) that promote neutrophil survival. Neutrophils only possess few, small mitochondria, and much of the Mcl-1 protein seems to be located in nuclear fractions. These observations provide the first evidence implicating a Bcl-2 family member in the regulation of neutrophil survival. Moreover, this work also provides a potential mechanism whereby cytokine-regulated gene expression regulates the functional lifespan of neutrophils and hence their ability to function for extended time periods during acute inflammation.

Human neutrophils possess a very short half-life because they constitutively undergo apoptosis. Cytokines, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), and other agents can rescue neutrophils from apoptosis but the molecular mechanisms involved in this rescue are undefined. Here, we show by Western blotting that human neutrophils do not express Bcl-2 or Bcl-X but constitutively express Bax. However, cellular levels of these proteins are unaffected by agents which either accelerate or delay neutrophil apoptosis. In contrast, neutrophils express the antiapoptotic protein Mcl-1 and levels of this protein correlate with neutrophil survival. Thus, cellular levels of Mcl-1 decline as neutrophils undergo apoptosis and are enhanced by agents (eg, GM-CSF, interleukin-1β, sodium butyrate, and lipopolysaccharide) that promote neutrophil survival. Neutrophils only possess few, small mitochondria, and much of the Mcl-1 protein seems to be located in nuclear fractions. These observations provide the first evidence implicating a Bcl-2 family member in the regulation of neutrophil survival. Moreover, this work also provides a potential mechanism whereby cytokine-regulated gene expression regulates the functional lifespan of neutrophils and hence their ability to function for extended time periods during acute inflammation.

Human neutrophils constitutively undergo apoptosis, process which is critical for the successful resolution of inflammation by the safe removal of effete cells. A wide variety of agents can modulate neutrophil apoptosis and these act through multiple and complex receptor-signalling pathways. Whilst these pathways can be initiated via distinct cell surface receptors, many downstream intracellular pathways can converge, use common molecules or trigger similar cellular activities, such as activation of caspases and transcription factors. The cell surface receptors, TNFR and Fas both trigger apoptosis in certain cell types, including neutrophils. However, TNF receptors also activate survival mechanisms in human neutrophils. This review summarises current knowledge about the regulation of neutrophil apoptosis via death receptors, the molecular components involved in signalling and potential therapeutic targets that are based on death receptors or their signalling pathways.

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