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

Published inMolecular immunology, vol. 45, no. 12, p. 3419-3427
Publication date2008
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
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. 3419–3427. doi: 10.1016/j.molimm.2008.04.001
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Article (Accepted version)
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Identifiers
ISSN of the journal0161-5890
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