One of the most intriguing gaps in our understanding of how neutrophils work concerns the mechanism by which the oxidase response in these cells is" primed'. In the primed state, there is no increase in oxidase activity, yet subsequent stimulation provokes a response that is larger than in nonprimed, activated cells. Thus, neutrophils exist in one of three states: quiescent, primed or active. Individual primed cells may be thought of as being'ready to go'but awaiting further stimulus before the oxidase response is elicited. The primed neutrophils are thus held at" amber', awaiting" green'before activity is triggered. Here, Maurice Hallett and Darren Lloyds suggest a molecular basis for the signals that say'amber" but not" green'.

The intracellular signalling route for activation of the oxidase response in neutrophils is becoming well established. Following stimulation of the cells with agonists that activate the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, there is a tenfold increase in the concentration of cytosolic free Ca 2+. At the level of the individual cell, this rise correlates with the activation of the oxidase 1. Furthermore, inhibition of this Ca 2÷ signal prevents oxidase activation, with an apparent ko. 5 (ie the concentration that gives half the maximum response) for activation of approximately 0.5~ M Ca 2÷(Ref. 2). Thus, a rise in cytosolic free Ca 2÷ is the key signalling event for activation. The identity of the targets for the raised cytosolic free Ca 2+ remain unclear, but may include protein kinase C (PKC) and calmodulin-dependent kinases. However, the evidence for these candidates remains scant. Although the transition of neutrophils from a resting to an active state has been widely studied, the transitions from resting to'primed'and from primed to active have received less attention. Nevertheless, data have begun to accumulate on the intracellular changes that accompany'priming', and these have led to new hypotheses concerning how the oxidase is triggered. Not only do these hypotheses relate to an understanding of how priming occurs, but they also give new insights into the possible mechanisms of activation of the oxidase system.