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Open Access Highly Accessed Research article

Innate immunity triggers IL-32 expression by fibroblast-like synoviocytes in rheumatoid arthritis

Ghada Alsaleh12, Laetitia Sparsa12, Emmanuel Chatelus12, Mathieu Ehlinger3, Jacques-Eric Gottenberg12, Dominique Wachsmann12* and Jean Sibilia12

Author Affiliations

1 EA3948, Laboratoire Physiopathologie des Arthrites, Université de Strasbourg, UFR Sciences Pharmaceutiques, 74 route du Rhin, 67401 Illkirch, France

2 Département de Rhumatologie, Hôpitaux Universitaires de Strasbourg, avenue Molière, Strasbourg Hautepierre 67200, France

3 Département d'Orthopédie, Hôpitaux Universitaires de Strasbourg, Strasbourg Hautepierre 67200, France

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Arthritis Research & Therapy 2010, 12:R135  doi:10.1186/ar3073

Published: 8 July 2010

Abstract

Introduction

Interleukin-32 (IL-32) is a recently described cytokine that is a strong inducer of pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, IL-1β, IL-6, and IL-8. The expression of this cytokine is highly increased in the rheumatoid synovium and correlated with the severity of joint inflammation. Little is known regarding the innate immune-related regulation of IL-32 by fibroblast-like synoviocytes (FLSs). We therefore investigated the effect of innate immune stimulation by ligands of Toll-like receptor (TLR)2, TLR3, and TLR4, and cytokines such as TNF-α and interferon (IFN)-γ, on IL-32 expression by FLSs.

Methods

FLSs were isolated from patients with rheumatoid arthritis (RA) according to the ACR criteria. Quantitative RT-PCR, confocal analysis, and ELISA were performed to evaluate IL-32 mRNA induction and IL-32 release by FLSs stimulated with TLR2 (BLP), TLR3 (poly I:C), and TLR4 (lipopolysaccharide) ligands, TNF-α and IFN-γ.

Results

TLR2, -3, and -4 ligands as well as IFN-γ and TNF-α induced IL-32 β, γ and δ mRNA expression by RA FLSs. Mature IL-32 was expressed intracellularly and released by cells stimulated with the various activators. The IL-32α isoform was expressed intracellularly in response to TNF-α and poly I:C and not released in culture supernatants. Stimulation of FLS with TNF-α, BLP, lipopolysaccharide, or poly I:C concomitant with IFN-γ increased IL-32 expression compared with stimulation with IFN-γ alone.

Conclusions

IL-32 synthesis by FLSs is tightly regulated by innate immunity in rheumatoid arthritis. Thus TNF-α, IFN-γ, double-strand RNA, hyaluronic acid, or other damage-associated molecular patterns (DAMPs), highly secreted in synovial tissues of RA patients, might trigger IL-32 secretion by FLSs. IL-32 might therefore represent a relevant therapeutic target in RA.