NDLI: TLR costimulation causes oxidative stress with unbalance of proinflammatory and anti-inflammatory cytokine production.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Lavieri, Rosa Castellani, Patrizia Rubartelli, Anna Delfino, Laura Carta, Sonia Piccioli, Patrizia
Description	Country affiliation: Italy Author Affiliation: Lavieri R ( Unità di Biologia Cellulare, IRCCS Azienda Ospedaliera Universitaria San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, 16132 Genoa, Italy.); Piccioli P ( Unità di Biologia Cellulare, IRCCS Azienda Ospedaliera Universitaria San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, 16132 Genoa, Italy.); Carta S ( Unità di Biologia Cellulare, IRCCS Azienda Ospedaliera Universitaria San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, 16132 Genoa, Italy.); Delfino L ( Unità di Biologia Cellulare, IRCCS Azienda Ospedaliera Universitaria San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, 16132 Genoa, Italy.); Castellani P ( Unità di Biologia Cellulare, IRCCS Azienda Ospedaliera Universitaria San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, 16132 Genoa, Italy.); Rubartelli A ( Unità di Biologia Cellulare, IRCCS Azienda Ospedaliera Universitaria San Martino, IST Istituto Nazionale per la Ricerca sul Cancro, 16132 Genoa, Italy anna.rubartelli@hsanmartino.it.)
Abstract	IL-1ß acts in concert with anti-inflammatory cytokines, in particular, IL-1R antagonist (IL-1Ra), to ensure the correct development and outcome of the inflammation: imbalance in the IL-1ß/IL-1Ra ratio is implicated in many human diseases and may lead to dramatic consequences. In this article, we show that single TLR engagement induces IL-1ß and, with a little delay, IL-1Ra. Differently, costimulation of TLR2, TLR4, and TLR7/8 enhances IL-1ß secretion but severely inhibits IL-1Ra production. The IL-1ß/IL-1Ra unbalance after activation of multiple TLRs depends on the insurgence of oxidative stress, because of enhanced production of reactive oxygen species and failure of the antioxidant systems. Increased reactive oxygen species levels increase ATP externalization by monocytes, resulting in enhanced inflammasome activation and IL-1ß secretion. Oxidative stress then induces cell responses to stress, including inhibition of protein synthesis, which, in turn, is responsible for the impaired production of IL-1Ra. IL-1Ra secretion is restored by exogenous antioxidants that oppose oxidative stress. Similar effects are evident also on other cytokines: TNF- is induced, whereas IL-6 is inhibited by costimulation. Our findings provide a molecular basis to the imbalance between proinflammatory and regulatory cytokine circuits that occur in various pathologic conditions, and suggest new strategies for controlling inflammation.
ISSN	00221767
e-ISSN	15506606
Journal	The Journal of Immunology
Issue Number	11
Volume Number	192
Language	English
Publisher	The American Association of Immunologists
Publisher Date	2014-06-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Anti-inflammatory Agents Immunology Inflammation Mediators Interleukin 1 Receptor Antagonist Protein Oxidative Stress Toll-like Receptors Cytokines Inflammasomes Reactive Oxygen Species Agonists Research Support, Non-u.s. Gov't Discipline Immunology
Content Type	Text
Resource Type	Article
Subject	Immunology and Allergy Immunology

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