Pharmacological inhibition of PI3K class III enhances the production of pro- and anti-inflammatory cytokines in dendritic cells stimulated by TLR agonists

The phosphatidylinositol 3-kinase (PI3K) pathway is known to down-regulate inflammatory cytokine responses in dendritic cells and macrophages stimulated with TLR agonists. This is due to class I PI3Ks causing the activation of Akt, which in turn inactivates GSK3, a kinase that promotes the transcription of IL-12 and represses that of anti-inflammatory IL-10. Using bone marrow-derived dendritic cells we find that whereas pharmacological inhibition of Akt or GSK3 has the expected effects on these cytokines, the widely used PI3K inhibitor wortmannin causes a paradoxical increase in the production of IL-10. Wortmannin inhibits all PI3K classes, including PI3K class III, involved in endosomal function and autophagy, for which specific inhibitors were until recently not available. Using inhibitors specific for PI3K class III vs class I, we show that whereas inhibition of class I PI3K has the expected opposing effects on IL-10 and IL-12 production, inhibition of class III PI3K enhances the production of both of these, plus further cytokines. This explains the paradoxical inhibition of IL-10 production by wortmannin.