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Differential regulation of cytokine production by PI3Kdelta in human monocytes upon acute and chronic inflammatory conditions |
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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/metabolism — Acute Disease — Cell Line — Cell Separation — Chronic Disease — Cytokines/biosynthesis — Enzyme Activation/drug effects — Glycogen Synthase Kinase 3/antagonists & inhibitors — Humans — Inflammation/enzymology — Interleukin 1 Receptor Antagonist Protein/biosynthesis — Interleukin-1beta/biosynthesis — Interleukin-6/biosynthesis — Isoenzymes/antagonists & inhibitors — Lipopolysaccharides/pharmacology — Lymphocyte Activation/drug effects — Monocytes/drug effects/enzymology/immunology — Phosphorylation/drug effects — Protein Kinase Inhibitors/pharmacology — Proto-Oncogene Proteins c-akt/metabolism — Time Factors — Tumor Necrosis Factor-alpha/biosynthesis | |
Identifiers | PMID: 18471882 | |
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Research group | Inflammation et allergie (874) | |
Citation (ISO format) | MOLNARFI, Nicolas et al. Differential regulation of cytokine production by PI3Kdelta in human monocytes upon acute and chronic inflammatory conditions. In: Molecular immunology, 2008, vol. 45, n° 12, p. 3419-27. doi: 10.1016/j.molimm.2008.04.001 https://archive-ouverte.unige.ch/unige:1102 |