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Differential regulation of cytokine production by PI3Kdelta in human monocytes upon acute and chronic inflammatory conditions

Published in Molecular Immunology. 2008, vol. 45, no. 12, p. 3419-27
Abstract Deregulated production of cytokines, including IL-1beta, 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-1beta and its specific inhibitor secreted IL-1 receptor antagonist (sIL-1Ra) by human monocytes. Here we show that in contrast with PI3Kalpha, beta and gamma, PI3Kdelta accounts for most of the PI3K-dependent signaling ruling the production of IL-1beta, 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, PI3Kdelta 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 PI3Kdelta regulated cytokine transcript expression through the phosphorylation/inactivation of glycogen synthase kinase-3beta (GSK3beta). The blockade of GSK3beta displayed inverse effects to those of PI3Kdelta 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, PI3Kdelta represents a potential therapeutic target specific to chronic/sterile inflammatory conditions.
Keywords 1-Phosphatidylinositol 3-Kinase/antagonists & inhibitors/metabolismAcute DiseaseCell LineCell SeparationChronic DiseaseCytokines/biosynthesisEnzyme Activation/drug effectsGlycogen Synthase Kinase 3/antagonists & inhibitorsHumansInflammation/enzymologyInterleukin 1 Receptor Antagonist Protein/biosynthesisInterleukin-1beta/biosynthesisInterleukin-6/biosynthesisIsoenzymes/antagonists & inhibitorsLipopolysaccharides/pharmacologyLymphocyte Activation/drug effectsMonocytes/drug effects/enzymology/immunologyPhosphorylation/drug effectsProtein Kinase Inhibitors/pharmacologyProto-Oncogene Proteins c-akt/metabolismTime FactorsTumor Necrosis Factor-alpha/biosynthesis
Stable URL http://archive-ouverte.unige.ch/unige:1102
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PMID: 18471882
Research group Inflammation et allergie (874)
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