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and Secreted IL-1 Receptor Antagonist Production by Phosphatidylinositide-3 Kinases in Human Monocytes Activated by Lipopolysaccharides or Contact with T Cells1
Division of Immunology and Allergy, Clinical Immunology Unit, Department of Internal Medicine, Faculty of Medicine, University Hospital, Geneva, Switzerland
The unbalanced production of IL-1
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-. In this study, we addressed the question of PI3K involvement in the production of IL-1 and sIL-1Ra in monocytes activated by cellular contact with stimulated T cells (mimicked by CHAPS-solubilized membranes of stimulated T cells (CEsHUT)), and a crude preparation of LPS, to compare stimuli relevant to chronic/sterile and acute/infectious inflammation, respectively. In monocytes activated by either CEsHUT 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-1 protein in both CEsHUT- and LPS-activated monocytes, the enhancement being drastically higher in the former. This was not due to changes in IL-1 mRNA steady-state levels or transcript stability, but to the involvement of PI3Ks in the repression of IL-1 secretion. The downstream PI3K effector, Akt, was implicated in this process. The present results demonstrate that PI3Ks are involved in the inhibition of IL-1 secretion and in the induction of sIL-1Ra production in human blood monocytes by controlling different mechanisms in conditions mimicking chronic/sterile (CEsHUT) and acute/infectious (LPS) inflammation.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Grant 3200-068286.02 from the Swiss National Science Foundation and a grant from the Swiss Society for Multiple Sclerosis.
2 Address correspondence and reprint requests to Dr. Danielle Burger, Clinical Immunology Unit, BB-4866, University Hospital, 24 rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland. E-mail address: danielle.burger{at}hcuge.ch
3 Abbreviations used in this paper: sIL-1Ra, secreted IL-1R antagonist; RA, rheumatoid arthritis; CEsHUT, CHAPS-solubilized, isolated membranes of stimulated HUT-78 cells; CEsT, CHAPS-solubilized, isolated membranes of stimulated peripheral blood T lymphocytes; ActD, actinomycin D; ARE, AU-rich element.
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