Neutrophils are a central component of the innate immune system and are beneficially recruited to the lungs in response to infection or injury. However, if neutrophil activity persists inappropriately this can perpetuate inflammation leading to disease. Apoptosis ensures potentially injurious inflammatory cells are recognised for removal by macrophages resulting in successful resolution of inflammation(1). Recently, cyclin-dependent kinase inhibitors (CDKi) such as R-roscovitine have been shown to induce neutrophil apoptosis leading to improved resolution in animal models of inflammation(2). Neutrophil lifespan can be prolonged by the gram negative membrane component lipopolysaccharide (LPS)(3). Therefore we investigated the gram positive bacterial component (lipoteichoic acid (LTA)) on prolonging neutrophil survival by delaying apoptosis and whether this could be overcome by the novel CDKi, AT7519(4). We also investigated the effect of AT7519 on the key endogenous neutrophil survival protein, Mcl-1. Human neutrophils were isolated from peripheral blood and cultured over time in the presence of increasing LTA concentrations (0-30µg/ml) ± AT7519 (Astex Therapeutics). Neutrophil viability and apoptosis were assessed by flow cytometry (annexinV and propidium iodide staining) and morphological analysis while Mcl-1 levels were analysed by western blotting(5). Values are mean ± SEM with statistical analysis performed using two-way ANOVA with a Bonferroni multiple comparison post hoc test. LTA enhanced neutrophil viability in a time- and concentration-dependent manner by inhibition of apoptosis. For example, by 20h in culture neutrophil survival was 16.2±2.2% which more than doubled in the presence of 30µg/ml LTA (36.6±7.1%, n=4; p<0.001). AT7519 induced a time dependent induction of neutrophil apoptosis which was able to override the survival effects of LTA. For example, at 8h rates of apoptosis were 23.2±3.5% in control, 11.5±3.1% in LTA (30µg/ml), 70.8±2.4% in AT7519 (1µM) and 64.4±2.4% in combined LTA and AT7519 (n=4, p<0.01 for control vs. AT7519 and LTA). Induction of apoptosis by AT7519 was associated with down-regulation of Mcl-1, even in the presence of LTA, as assessed by western blotting (n=3). This study showed that LTA enhances neutrophil longevity in vitro in a concentration and time-dependent manner by preventing apoptosis whereas the CDKi, AT7519, induces neutrophil apoptosis and overcomes the anti-apoptotic effect of LTA by a rapid down-regulation of Mcl-1. CDKi drugs can effectively “turn-off” neutrophils by driving apoptosis despite the presence of a gram positive pro-inflammatory stimulus. As such, CDKi drugs like AT7519 may have pro-resolution, anti-inflammatory therapeutic potential in disease states such as pneumonia where gram positive infections predominate.