title: Opposite regulation of IL-1beta and secreted IL-1 receptor antagonist production by phosphatidylinositide-3 kinases in human monocytes activated by lipopolysaccharides or contact with T cells.
abstract: The unbalanced production of IL-1beta and its natural, specific inhibitor, the secreted IL-1R antagonist (sIL-1Ra), plays an important role in chronic/sterile inflammation. Relevant to this condition is direct cellular contact with stimulated T cells which is a potent inducer of cytokine production in human monocytes/macrophages. We previously demonstrated that activation of PI3Ks is a prerequisite of the transcription of the sIL-1Ra gene in human monocytes activated by IFN-beta. In this study, we addressed the question of PI3K involvement in the production of IL-1beta 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 a crude preparation of LPS, to compare stimuli relevant to chronic/sterile and acute/infectious inflammation, respectively. In monocytes activated by either CE(sHUT) or LPS, the inhibition of PI3Ks abrogated sIL-1Ra transcript expression and sIL-1Ra production, demonstrating that PI3Ks control the induction of sIL-1Ra gene transcription. In contrast, PI3K inhibition increased the production of IL-1beta protein in both CE(sHUT)- and LPS-activated monocytes, the enhancement being drastically higher in the former. This was not due to changes in IL-1beta mRNA steady-state levels or transcript stability, but to the involvement of PI3Ks in the repression of IL-1beta secretion. The downstream PI3K effector, Akt, was implicated in this process. The present results demonstrate that PI3Ks are involved in the inhibition of IL-1beta secretion and in the induction of sIL-1Ra production in human blood monocytes by controlling different mechanisms in conditions mimicking chronic/sterile (CE(sHUT)) and acute/infectious (LPS) inflammation.
authors.affiliation: Division of Immunology and Allergy, Clinical Immunology Unit, Department of Internal Medicine, Faculty of Medicine, University Hospital, Geneva, Switzerland.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Molnarfi
authors.forename: Lyssia
authors.initials: L
authors.lastname: Gruaz
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Dayer
authors.forename: Danielle
authors.initials: D
authors.lastname: Burger
mesh_terms: D002460:Cell Line; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger