Neutrophils are generally the first leukocytes to arrive at sites of inflammation or injury, where they release a variety of inflammatory mediators, which contribute to shaping the ensuing immune response. Here, we show that in neutrophils exposed to physiological stimuli (i.e. LPS and TNF-a), inhibition of the PI3K signaling pathway impairs the synthesis and secretion of IL-8, Mip-1a, and Mip-1b. Further investigation showed that Mip-1a and Mip-1b gene transcription was similarly decreased, whereas IL-8 transcription and steadystate mRNA levels were unaffected. Accordingly, PI3K inhibition had no impact on NF-jB or C/EBP activation, which are essential for IL-8 transcription, but the basis for this selective inhibition of chemokine transcription remains elusive. We nevertheless identified translational targets of the PI3K pathway (S6, S6 kinase, 4E-BP1). Inhibitor studies and overexpression experiments further established that the various effects of PI3K on chemokine production can be ascribed to p85a and p110d subunits. Finally, we show that in LPS-and TNF-activated neutrophils, PI3K acts downstream of the kinases p38 MAPK and TAK1 . Given the importance of neutrophils and their products in numerous chronic inflammatory disorders, the PI3K pathway could represent an attractive therapeutic target.

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