Elsevier

Cytokine

Volume 41, Issue 1, January 2008, Pages 16-23
Cytokine

The expression of IL-20 and IL-24 and their shared receptors are increased in rheumatoid arthritis and spondyloarthropathy

https://doi.org/10.1016/j.cyto.2007.10.004Get rights and content

Abstract

The purpose of this study was to analyze the expression of the two proinflammatory cytokines IL-20 and IL-24 and their shared receptors in rheumatoid arthritis and spondyloarthropathy. IL-20 was increased in plasma of rheumatoid arthritis patients compared with osteoarthritis patients and IL-24 was increased in synovial fluid and plasma of rheumatoid arthritis and spondyloarthropathy patients compared with osteoarthritis patients. IL-20 and IL-24 mRNA was only present at low levels in the synovium. In the synovial membrane, IL-20 protein was present in mononuclear cells and neutrophil granulocytes whereas IL-24 protein was observed in endothelial cells and mononuclear cells. IL-20 receptor type 1 and IL-22 receptor were expressed by granulocytes in the synovial fluid. In synovial fluid mononuclear cell cultures, stimulation with recombinant human IL-20 or recombinant human IL-24 induced monocyte chemoattractant protein 1 (CCL2/MCP-1) secretion, but not tumour necrosis factor α mRNA synthesis or IL-6 secretion. Both IL-20 and IL-24 showed correlations to CCL2/MCP-1 in plasma from rheumatoid arthritis and spondyloarthropathy patients. This study associates IL-20 and IL-24 to the synovium of rheumatoid arthritis and spondyloarthropathy and results indicate that the two cytokines contribute to disease pathogenesis through recruitment of neutrophil granulocytes and induction of CCL2/MCP-1.

Introduction

Rheumatoid arthritis (RA) is an inflammatory disease that causes progressive joint damage and disability. In this inflammatory process, cytokines including IL-1, IL-6, IL-8, IL-10, monocyte chemoattractant protein 1 (CCL2/MCP-1), and tumour necrosis factor (TNFα) play a prominent role [1], [2], [3]. Spondyloarthropathy (SpA) comprises a group of related diseases characterized by spinal inflammation and peripheral joint oligoarthritis often including cutaneous manifestations. The role of cytokines is better characterized in RA than in SpA. However, TNFα blockers have been shown to be beneficial in the treatment of both psoriatic arthritis and ankylosing spondylitis suggesting a role for cytokines in the pathogenesis of these diseases [4], [5], [6], [7].

IL-20 and IL-24 are two recently identified members of the IL-10 family of cytokines [8]. IL-20 expression has predominantly been described in monocytes [9], and keratinocytes [10], whereas IL-24 expression has primarily been found in macrophages [11], [12], monocytes, T cells [9], and keratinocytes [10]. IL-20 and IL-24 signal through the receptor complexes IL-20 receptor type 1 (IL-20R1)/IL-20 receptor type 2 (IL-20R2) and IL-22 receptor (IL-22R)/IL-20R2 [13], [14].

IL-20 has primarily been associated with psoriasis, as IL-20 expression in transgenic mice has been shown to cause skin abnormalities very similar to those observed in psoriasis [15]. Furthermore, the mRNA of IL-20 and of its three receptor subunits have been found in lesional psoriatic skin [16], [17], [18]. IL-24, also known as melanoma differentiation-associated gene 7, was discovered due to its ability to induce apoptosis in melanoma cells [19]. Furthermore, IL-24 has been shown to be expressed at increased levels in psoriasis [16].

The involvement of IL-20 and IL-24 in rheumatic diseases is not clarified. IL-20 and its three receptor subunits have been found in the synovial membrane of patients with RA [20], [21]. IL-20 has also been shown to induce cytokine secretion in synovial fibroblasts, neutrophil chemotaxis, synovial fibroblast migration, and endothelial cell proliferation. Interestingly, the soluble IL-20R1 has been found to decrease the severity of collagen induced arthritis in rats suggesting that cytokines, which bind this receptor, are important in the pathogenesis of arthritis [20].

In this study, synovial fluid, plasma, and synovial membranes from RA and SpA patients were studied. Osteoarthritis (OA) patients served as non-inflammatory disease controls while healthy volunteers were included as normal controls. IL-20 and IL-24 levels were measured, the cellular sources and targets of IL-20 and IL-24 were studied and the effect of IL-20 and IL-24 on cytokine production was analyzed. This study provides new insight into the role of IL-20 in rheumatic diseases and presents the first association between IL-24 and these diseases.

Section snippets

Patients and samples

Synovial fluid and plasma were collected from patients with RA (n = 24) and SpA (n = 22). Subgroups included under the category SpA were psoriatic arthritis (n = 11), reactive arthritis (n = 2), enteropathic arthritis associated with inflammatory bowel disease (n = 2), and undifferentiated spondyloarthritis (n = 7). The inclusion criteria were the requirement of therapeutic arthrocenthesis and the absence of anti-TNFα treatment. Patients with RA and OA were diagnosed in accordance with the criteria

IL-20 and IL-24 levels in synovial fluid and plasma

The levels of IL-20 and IL-24 in synovial fluid and plasma from patients with RA, SpA, and OA and plasma from normal healthy volunteers were measured by ELISA. In synovial fluid there were no differences in the levels of IL-20 between the three groups. IL-20 in plasma from RA patients (282 pg/ml (134–438 pg/ml)) was significantly higher than in plasma from OA patients (124 pg/ml (110–147 pg/ml)) (P = 0.006) (Fig. 2A).

IL-24 in synovial fluid from both RA (2.25 ng/ml (0–8.21 ng/ml)) and SpA (3.81 ng/ml

Discussion

This study is the first to investigate the expression profile of IL-20 in SpA and provides the first association between IL-24 and rheumatic diseases. The results indicate interesting and distinct roles for IL-20 and IL-24 in RA and SpA. IL-20 and IL-24 levels in RA and SpA patients were increased 1.5- to 2.5-fold in comparison with non-inflammatory disease controls and normal controls. RA and SpA patients had similar levels of IL-20 and IL-24. The level of IL-24 was around 10 times higher than

Acknowledgments

We thank Eva Lykke Petersen from the Institute of Medical Microbiology and Immunology for excellent technical assistance, Jes Thorn Clausen from Novo Nordisk A/S for donation of antibodies and cytokines, the Danish Rheumatism Association, the Danish Psoriasis Association. Tue Wenzel Kragstrup was supported by a grant from the Danish Medical Research Council (271-06-0014).

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