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: Nicolas Molnarfi, Lyssia Gruaz, Jean-Michel Dayer, Danielle Burger
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 178 Issue 1 Pg. 446-54 (Jan 01 2007) ISSN: 0022-1767 [Print] United States
• PMID: 17182583 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin 1 Receptor Antagonist Protein
• Interleukin-1beta
• Lipopolysaccharides
• Phosphoinositide-3 Kinase Inhibitors
• RNA, Messenger
• Proto-Oncogene Proteins c-akt

Topics

• Cell Line
• Down-Regulation
• Gene Expression Regulation
• Humans
• Interleukin 1 Receptor Antagonist Protein (genetics, metabolism)
• Interleukin-1beta (genetics, metabolism)
• Lipopolysaccharides (pharmacology)
• Monocytes (drug effects, immunology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA Stability
• RNA, Messenger (metabolism)
• T-Lymphocytes (immunology)
• Transcription, Genetic
• Up-Regulation