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Title

Differential regulation of cytokine production by PI3Kdelta in human monocytes upon acute and chronic inflammatory conditions
Authors
Molnarfi, Nicolas
Brandt, Karim
Gruaz, Lyssia
Dayer, Jean-Michel
Burger, Danielle
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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Article (Accepted version) (898 Kb) - document accessible for UNIGE members only Limited access to UNIGE
Structures
Faculté de médecine / Section de médecine clinique / Département de médecine
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

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Deposited on : 2009-03-06

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