Differential regulation of cytokine production by PI3Kδ in human monocytes upon acute and chronic inflammatory conditions

Abstract

Deregulated production of cytokines, including IL-1β, IL-6 and TNF plays an important role in chronic inflammation. Relevant to this condition, direct cellular contact with stimulated T cells is a potent inducer of cytokine production in human monocytes/macrophages. We previously demonstrated that PI3Ks regulate differential production of IL-1β and its specific inhibitor secreted IL-1 receptor antagonist (sIL-1Ra) by human monocytes. Here we show that in contrast with PI3Kα, β and γ, PI3Kδ accounts for most of the PI3K-dependent signaling ruling the production of IL-1β, IL-6, TNF and sIL-1Ra in monocytes activated by cellular contact with stimulated T cells (mimicked by CHAPS-solubilized membranes of stimulated T cells, CE sHUT) and lipopolysaccharides (LPS); the latter stimuli being relevant to chronic/sterile and acute/infectious inflammation, respectively. Interestingly, PI3Kδ activity dampened the production of pro-inflammatory cytokines in LPS-activated monocytes, but induced it in CE sHUT-activated cells. In both CE sHUT- and LPS-activated monocytes PI3Kδ regulated cytokine transcript expression through the phosphorylation/inactivation of glycogen synthase kinase-3β (GSK3β). The blockade of GSK3β displayed inverse effects to those of PI3Kδ blockade. Thus, by displaying opposite functions in conditions mimicking chronic/sterile and acute/infectious inflammation, i.e., by repressing pro-inflammatory cytokine expression in LPS-activated monocytes but inducing such mediators in T cell contact-activated monocytes, PI3Kδ represents a potential therapeutic target specific to chronic/sterile inflammatory conditions.