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

Nicolas Molnarfi, Karim J Brandt, Lyssia Gruaz, Jean-Michel Dayer, Danielle Burger

Division of Immunology and Allergy, Clinical Immunology Unit, Hans Wilsdorf Laboratory, Department of Internal Medicine, University Hospital and School of Medicine, University of Geneva, 24 rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland.

Molecular immunology 2008 Jul

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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.

Citation

Nicolas Molnarfi, Karim J Brandt, Lyssia Gruaz, Jean-Michel Dayer, Danielle Burger. Differential regulation of cytokine production by PI3Kdelta in human monocytes upon acute and chronic inflammatory conditions. Molecular immunology. 2008 Jul;45(12):3419-27