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* Institut de Biochimie et Biophysique Moléculaire et Cellulaire, Université Paris-Sud, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8619, Orsay, France;
Biochemical Pharmacology, University of Konstanz, Konstanz, Germany,
Institut Pasteur, Unité de Défense Innée et Inflammation, INSERM Unité 874, Paris, France;
Unité de Formation et de Recherche Sciences du Vivant, Université Paris Diderot 7, Paris, France; and
¶ Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom
Bacterial LPS triggers monocytes and macrophages to produce several inflammatory cytokines and mediators. However, once exposed to LPS, they become hyporesponsive to a subsequent endotoxin challenge. This phenomenon is defined as LPS desensitization or tolerance. Previous studies have identified some components of the biochemical pathways involved in negative modulation of LPS responses. In particular, it has been shown that the IL-1R-related protein ST2 could be implicated in LPS tolerance. The natural ligand of ST2 was recently identified as IL-33, a new member of the IL-1 family. In this study, we investigated whether IL-33 triggering of ST2 was able to induce LPS desensitization of mouse macrophages. We found that IL-33 actually enhances the LPS response of macrophages and does not induce LPS desensitization. We demonstrate that this IL-33 enhancing effect of LPS response is mediated by the ST2 receptor because it is not found in ST2 knockout mice. The biochemical consequences of IL-33 pretreatment of mouse macrophages were investigated. Our results show that IL-33 increases the expression of the LPS receptor components MD2 (myeloid differentiation protein 2) and TLR-4, the soluble form of CD14 and the MyD88 adaptor molecule. In addition, IL-33 pretreatment of macrophages enhances the cytokine response to TLR-2 but not to TLR-3 ligands. Thus, IL-33 treatment preferentially affects the MyD88-dependent pathway activated by the TLR.
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1 This work was supported by the Marie Curie Program "Pulmo-Net" (MRTN-CT2004-512229), the "Centre National de la Recherche Scientifique" and University Paris-Sud. E.G.d.P. is an Early Stage Researcher and I.G.-V. was an Experienced Researcher funded by the Marie Curie Program. E.G.d.P. was also supported by a fellowship from the Fundación Caja Madrid. Q.E. was supported by a fellowship from La Fondation pour la Recherche Médicale.
2 Q.E. and E.G.d.P. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Jean M. Kanellopoulos, Laboratoire Activation Cellulaire et Transduction des Signaux, Institut de Biochimie et Biophysique Moléculaire et Cellulaire, Univ Paris-Sud, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8619, Bâtiment 430, 91405 Orsay Cedex, France; E-mail address: jean.kanellopoulos{at}u-psud.fr
4 Abbreviations used in this paper: TRIF, Toll/IL-1R domain-containing adapter inducing IFN-β; iNKT, invariant NKT; KO, knockout; LTA, lipoteichoic acid; poly(I:C), polyinosinic:polycytidylic acid; PVDF, polyvinylidene difluoride; qPCR, quantitative real-time PCR; sCD14, soluble CD14; SIGIRR, single Ig IL-1R-related; wt, wild type.
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