IL-27-producing CD14+ cells infiltrate inflamed joints of rheumatoid arthritis and regulate inflammation and chemotactic migration
Highlights
► The IL-27 level in synovial fluid of RA is significantly higher than that of OA. ► IL-27 in RA joints is derived from CD14+ cells. ► IL-27+CD14+ cells significantly infiltrate into RA synovium. ► WSX-1 is ubiquitously expressed on RA synovium. ► IL-27 suppresses the production of IL-6 or CCL20 from RA fibroblast-like synoviocytes.
Introduction
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, manifesting as systemic inflammatory arthritis with hypertrophy of the synovium followed by the destruction of cartilage, bone, and joint structures. Several in vivo experimental autoimmune animal models and in vitro human studies have suggested that interleukin (IL)-17-secreting helper T (Th17) cells can be considered a critical mediator of RA with respect to tissue inflammation or bone resorption [1], [2], [3], [4]. Th17 cells specifically express chemokine receptor CCR6, and its ligand CCL20 recruits Th17 cells [1], [5]. An association of the dinucleotide polymorphism of the CCR6 gene (CCR6DNP) with RA susceptibility has been suggested [6].
IL-27 is a recently identified cytokine, which is structurally related to IL-12 as a heterodimeric cytokine, similar to IL-23 and IL-35. IL-27 is composed of Epstein–Barr virus-induced gene 3 (EBI3), a p40-related molecule, and IL-27p28, a p35-related molecule [7]. IL-27 is produced by antigen presenting cells (APCs) including dendritic cells (DCs) and monocytes, and is secreted as a heterodimer [8]. IL-27 is reported to be expressed at chronic inflammatory sites, such as synovial tissues in RA [9], skin lesions in psoriasis [10], inflamed intestine in Crohn’s disease, and granulomas in tuberculosis or sarcoidosis [11]. IL-27 suppresses the development of Th17 cells and the production of cytokines including IL-17A from activated CD4+ T cells by blocking RAR-related orphan receptor C (RORC) expression in humans and in several experimental animal models, while it induces Th1 differentiation [9], [12], [13], [14], [15].
IL-27 receptor (IL-27R) is also a heterodimer of WSX-1 (IL-27Rα), a homologue of IL-12Rβ2, and gp130, a component of the IL-6 receptor [16], [17]. Both components are coexpresssed in various human cell types, including monocytes, DCs, T cells, B cells, natural killer cells, mast cells and endothelial cells, and both components are required for the signal transduction of IL-27 [17]. Downstream of IL-27R, mainly STAT1 and STAT3 are activated [17], [18].
In a murine collagen-induced arthritis (CIA) model, administration of IL-27 reduces the amount of serum IL-6, cellular infiltration to the joints, synovial hyperplasia and joint erosion at the onset of the disease [9]. IL-27 also inhibits human receptor of NF-κB ligand (RANKL)-mediated osteoclastogenesis [19], [20]. These reports suggest protective roles for IL-27 in the pathogenesis of arthritis. In contrast, it is also reported that IL-27 possesses pathogenic roles in RA. In experimental animal models of adjuvant-induced arthritis and proteoglycan-induced arthritis, IL-27 is critically involved with the development of arthritis by inducing the differentiation of naïve T cells into interferon (IFN)-γ-producing Th1 cells [21], [22]. In humans, high concentrations of IL-27 induce the production of IL-6 and inflammatory chemokines from FLSs of established RA [23]. These conflicting reports reflect the complex functions of IL-27 in human immunology.
In this study, we investigated the source and role of IL-27 in RA. We show that IL-27-producing CD14+ cells significantly infiltrate RA synovium, and that physiological concentrations of IL-27 could have anti-inflammatory effects in several ways: both directly through the suppression of IL-6 production and possibly through Th1 differentiation; and indirectly by regulating recruitment of CCR6+ cells including Th17 cells through the suppression of CCL20 production. Our results suggest that IL-27 might be a potential therapeutic agent for RA.
Section snippets
Cytokines and reagents
Human recombinant tumor necrosis factor (TNF)-α, human recombinant IL-1β, human recombinant IL-6, human recombinant soluble IL-6 receptor (sIL-6R), and human recombinant IL-17A were purchased from PeproTech USA (Rocky Hill, NJ, USA). The following reagents were purchased from R&D Systems (Minneapolis, MN, USA): human recombinant IL-27, anti-human TCCR/WSX-1 antibody, isotype control IgG, human TCCR/WSX-1 Fc chimera, human IgG1 Fc, anti-human IL-27 antibody and isotype control IgG. Anti-human
IL-27 is expressed similarly in plasma of RA and OA patients and HV, but is significantly higher in RA synovial fluid than in OA synovial fluid
To investigate the possible contribution of IL-27 to the pathogenesis of RA, we measured the concentration of IL-27 in the synovial fluid from patients with RA or OA, and in plasma from HV or patients with RA or OA. The IL-27 level in synovial fluid of RA patients (mean 0.13 ng/ml; range 0.017–0.37 ng/ml) was significantly higher (P < 0.0005) than that in OA patients (mean 0.003 ng/ml; range 0–0.033 ng/ml) (Fig. 1). However, the concentrations of plasma IL-27 in RA patients (mean 0.45 ng/ml; range
Discussion
In this study, we showed that the concentration of IL-27 in plasma of RA and OA patients and HV was at most 1 ng/ml, while that in synovial fluid of RA and OA was at most 400 and 40 pg/ml, respectively (Fig. 1). Recently, IL-27 at 10–100 ng/ml was reported to activate RA FLSs as an inflammatory cytokine [23]. In our laboratory, a high concentration (100 ng/ml) of IL-27 tended to induce IL-6 production from RA FLSs. However, based on the detected concentration of IL-27 in plasma or synovial fluid,
Acknowledgments
This study was supported by health and Labor Science Research Grants for Research on Allergic Disease and Immunology from the Ministry of Health, Labor and Welfare (Grant No. 10103190). We thank J. Toguchida, T. Aoyama, and K. Yamamoto for technical support.
References (27)
- et al.
CCL20 produced in the cytokine network of rheumatoid arthritis recruits CCR6+ mononuclear cells and enhances the production of IL-6
Cytokine
(2009) - et al.
IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4(+) T cells
Immunity
(2002) - et al.
Advances in understanding the anti-inflammatory properties of IL-27
Immunol Lett
(2008) - et al.
Possible roles of IL-27 in the pathogenesis of psoriasis
J Invest Dermatol
(2010) - et al.
Cloning and characterization of a novel class I cytokine receptor
Biochem Biophys Res Commun
(1998) - et al.
Immature dendritic cell transdifferentiation into osteoclasts: a novel pathway sustained by the rheumatoid arthritis microenvironment
Blood
(2004) - et al.
Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model
J Exp Med
(2007) - et al.
IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist
Proc Natl Acad Sci U S A
(2003) - et al.
A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17
Nat Immunol
(2005) - et al.
IL-17 induces osteoclastogenesis from human monocytes alone in the absence of osteoblasts, which is potently inhibited by anti-TNF-alpha antibody: a novel mechanism of osteoclastogenesis by IL-17
J Cell Biochem
(2009)
A regulatory variant in CCR6 is associated with rheumatoid arthritis susceptibility
Nat Genet
Interleukin 27 attenuates collagen-induced arthritis
Ann Rheum Dis
Expression of IL-27 in human Th1-associated granulomatous diseases
J Pathol
Cited by (54)
IL-27 attenuates IL-23 mediated inflammatory arthritis
2023, Clinical ImmunologyIL-27 regulates autophagy in rheumatoid arthritis fibroblast-like synoviocytes via STAT3 signaling
2022, ImmunobiologyCitation Excerpt :High levels of synovial IL-27 expression have been reported in RA, and an adenoviral vector containing IL-27 mRNA has been shown to suppress synovitis, bone degeneration, and inflammation in a rodent collagen-induced arthritis model system (Shahrara et al.2011). IL-27-mediated signaling can also suppress RA-FLS-mediated production of inflammatory factors such as CCL20 and IL-6 (Tanida et al.2011), and mice deficient for IL-27R expression exhibit less severe experimental arthritis as compared to IL-27R+/+ mice (Cao et al.2007). IL-27 thus exerts broad regulatory roles in shaping the pathogenesis of RA in different model systems.
IL-27 and autoimmune rheumatologic diseases: The good, the bad, and the ugly
2020, International ImmunopharmacologyPredicting drug-free remission in rheumatoid arthritis: A prospective interventional cohort study
2019, Journal of AutoimmunityCitation Excerpt :We furthermore observe that IL-27 is associated with increased risk of flare following DMARD cessation. Indeed, IL-27 has been implicated in the pathogenesis of RA [51–55], though has also shown protective effects against experimentally-induced arthritis in murine models [56,57]. Our results suggest that further exploration of the mechanistic role of IL-27 in the context of arthritis flare may prove valuable.
Anti cytokine therapy in chronic inflammatory arthritis
2016, CytokineCitation Excerpt :Previously thought to enhance inflammation [74], there is increasing evidence the IL-27 has both pro- and anti-inflammatory roles. Increased levels of IL-27 have been measured in the synovial fluid of RA patients as compared to controls [75]. However, studies using the collagen-induced arthritis murine model have highlighted the therapeutic potential of IL-27, where both local and systemic IL-27 delivery ameliorates arthritis severity [76,77].