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Bruton’s Tyrosine Kinase Is Involved in miR-346-Related Regulation of IL-18 Release by Lipopolysaccharide-Activated Rheumatoid Fibroblast-Like Synoviocytes ¹

Ghada Alsaleh^*, Guillaume Suffert^2,3,, Noha Semaan^*,2, Tom Juncker^*, Laurent Frenzel^*, Jacques-Eric Gottenberg^*, Jean Sibilia^*, Sébastien Pfeffer^3,4, and Dominique Wachsmann^4,*

^* Laboratoire Physiopathologie des Arthrites, EA3432, Université Louis Pasteur de Strasbourg, Unité de Formation et de Recherche Sciences Pharmaceutiques, Illkirch, France and Departement de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Strasbourg Hautepierre, France; and Unité Propre de Recherche-Centre National de la Recherche Scientifique 2357, Institut de Biologie Moléculaire des Plantes, Strasbourg, France

MicroRNAs (miRNAs) have emerged as key players in the regulation of expression of target mRNAs expression. They have been associated with diverse biological processes, and recent studies have demonstrated that miRNAs play a role in inflammatory responses. We reported previously that LPS-activated fibroblast-like synoviocytes (FLS) isolated from rheumatoid arthritis (RA) patients express IL-18 mRNA but they do not release IL-18. Based on the observation that this inhibition was due to a rapid degradation of IL-18 mRNA, our group has conducted a study to identify miRNAs that could play a role in the "antiinflammatory" response of LPS-activated RA FLS. LPS challenge modulated the expression of 63 miRNAs as assessed by microarray analysis. Fifteen miRNAs were up-regulated, including miR-346, for which overexpression upon LPS treatment was validated by quantitative RT-PCR. We then transfected FLS with an antisense oligonucleotide targeting miR-346 and found that, in these conditions, IL-18 release could be measured upon LPS activation of FLS. Moreover, we also demonstrated that miR-346 indirectly regulated IL-18 release by indirectly inhibiting LPS-induced Bruton’s tyrosine kinase expression in LPS-activated RA FLS. These findings suggest that miRNAs function as regulators that help to fine-tune the inflammatory response in RA.

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 D.W.’s work was supported by grants from Bristol Myers Squibb, Roche, Pfizer, the Courtin Fundation, and the Caisse d’Assurance Maladie des Professions Libérales-Provinces. S.P.’s work is supported by the Agence Nationale de la Recherche and the Ligue contre le Cancer.

² G.S. and N.S. contributed equally to this work.

³ Current address: Architecture et Réactivité de l’ARN, Université de Strasbourg, Institut de Biologie Moléculaire et Cellulaire du Centre National de la Recherche Scientifique, 15 rue René Descartes, Strasbourg, France.

⁴ Address correspondence and reprint requests to Dr. Sébastien Pfeffer, Architecture et Réactivité de l’ARN, Institut de Biologie Moléculaire et Cellulaire-Centre National de la Recherche Scientifique, 15 rue René Descartes, 67084 Strasbourg, France. E-mail address: spfeffer{at}unistra.fr and Dr. Dominique Wachsmann, EA3432, Unité de Formation et de Recherche Sciences Pharmaceutiques, 74 route du Rhin, 67401 Illkirch, France. E-mail address: dominique.wachsmann{at}pharma.u-strasbg.fr

⁵ Abbreviations used in this paper: RA, rheumatoid arthritis; Btk, Bruton’s tyrosine kinase; FLS, fibroblast-like synoviocytes; LFM, leflunomide metabolite analog; miRNA, microRNA; PAMP, pathogen-associated molecular pattern; PRR, pattern recognition receptor; UTR, untranslated region.