Serum IL-40 is elevated in systemic sclerosis and is linked to disease activity, gastrointestinal involvement, immune regulation and fibrotic processes

IF 4.6 2区医学 Q1 Medicine

Arthritis Research & Therapy Pub Date : 2025-06-02 DOI:10.1186/s13075-025-03570-3

Adéla Navrátilová, Sabína Oreská, Hana Wünsch, Klára Mocová, Ondřej Kodet, Marian Rybar, Glenda Alquicer, Aneta Prokopcová, Viktor Bečvář, Radim Bečvář, Aneta Jiránková, Anna Bobrová, Kateřina Bobrová, Karel Pavelka, Jiří Vencovský, Ladislav Šenolt, Lucie Andrés Cerezo, Michal Tomčík

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引用次数: 0

Abstract

Interleukin 40 (IL-40) is a cytokine implicated in malignancies and rheumatic disorders. Its association with fibrotic mediators has been previously described. Since inflammation and fibrosis are hallmarks of systemic sclerosis (SSc), we aimed to analyze the role of IL-40 in SSc. IL-40 levels were analyzed in the serum of 90 SSc patients and 75 healthy controls (HCs). IL-40 expression in dermal biopsies from 5 SSc patients and 5 HCs was assessed via immunohistochemistry. IL-40 was analyzed in 39 SSc patients with interstitial lung disease treated with cyclophosphamide (CPA) and in 24 SSc patients with active progressive disease treated with rituximab (RTX). SSc activity was assessed by the European Scleroderma Study Group (ESSG) index. The effect of recombinant IL-40 on peripheral blood mononuclear cells (PBMCs) from 10 SSc patients was determined in vitro. IL-40 was analyzed in 24 individuals at risk of developing SSc (VEDOSS), who were categorized as progressors (n = 11) and nonprogressors (n = 13). IL-40 expression was elevated in the skin of SSc patients compared to HCs, particularly in fibroblasts and immune infiltrates. Serum IL-40 was increased in SSc compared to HCs (p < 0.0001) and was associated with ESSG (r = 0.372, p = 0.0005) and gastrointestinal involvement (p < 0.05). IL-40 correlated with serum IL-8 (r = 0.270, p = 0.019) and TGF-β1 (r = 0.301, p = 0.024) levels. In the CPA and RTX cohort, no significant changes in the serum IL-40 were observed upon treatment. Baseline and changes in IL-40 levels were associated with changes in several clinical parameters. IL-40 was elevated in patients at risk of SSc compared to HCs (p = 0.0003). No significant changes were observed in progressors vs. nonprogressors; however, IL-40 was associated with capillaroscopy findings (p < 0.05). IL-40 induced the upregulation of IL-6 (p = 0.002), MCP-1 (p = 0.002) and IL-10 (p = 0.002) in PBMCs from SSc patients in vitro. IL-40 was upregulated in the skin and serum of SSc patients and was associated with disease activity, gastrointestinal involvement and fibrotic mediators. Our in vitro findings indicate that IL-40 might be involved in the immune response and fibrotic processes in SSc.

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血清IL-40在系统性硬化症中升高，并与疾病活动性、胃肠道受累、免疫调节和纤维化过程有关

白细胞介素40 （IL-40）是一种与恶性肿瘤和风湿病有关的细胞因子。它与纤维化介质的关联先前已被描述过。由于炎症和纤维化是系统性硬化症（SSc）的标志，我们旨在分析IL-40在SSc中的作用。分析90例SSc患者和75例健康对照（hc）血清中IL-40水平。免疫组织化学方法检测5例SSc患者和5例hcc患者皮肤活检组织中IL-40的表达。对39例接受环磷酰胺（CPA）治疗的SSc间质性肺病患者和24例接受利妥昔单抗（RTX）治疗的SSc进行性活动性疾病患者进行IL-40分析。SSc活性通过欧洲硬皮病研究组（ESSG）指数进行评估。研究了重组IL-40对10例SSc患者外周血单个核细胞（PBMCs）的影响。对24例有SSc （VEDOSS）发病风险的患者进行IL-40分析，这些患者分为进展者（n = 11）和非进展者（n = 13）。与hcc患者相比，SSc患者皮肤中IL-40表达升高，特别是在成纤维细胞和免疫浸润中。SSc患者血清IL-40高于hcc患者（p < 0.0001），且与ESSG （r = 0.372, p = 0.0005）和胃肠道受累相关（p < 0.05）。IL-40与血清IL-8 （r = 0.270, p = 0.019）、TGF-β1 （r = 0.301, p = 0.024）水平相关。在CPA和RTX组中，治疗后血清IL-40未见明显变化。基线和IL-40水平的变化与几个临床参数的变化相关。与hcc患者相比，SSc患者IL-40升高（p = 0.0003）。进展者与非进展者未观察到显著变化；然而，IL-40与毛细血管镜检查结果相关（p < 0.05）。IL-40诱导体外SSc患者外周血中IL-6 （p = 0.002）、MCP-1 （p = 0.002）和IL-10 （p = 0.002）表达上调。IL-40在SSc患者的皮肤和血清中上调，并与疾病活动性、胃肠道受损伤和纤维化介质相关。我们的体外研究结果表明，IL-40可能参与了SSc的免疫反应和纤维化过程。

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来源期刊

Arthritis Research & Therapy RHEUMATOLOGY-

CiteScore

8.60

自引率

2.00%

发文量

261

审稿时长

14 weeks

期刊介绍： Established in 1999, Arthritis Research and Therapy is an international, open access, peer-reviewed journal, publishing original articles in the area of musculoskeletal research and therapy as well as, reviews, commentaries and reports. A major focus of the journal is on the immunologic processes leading to inflammation, damage and repair as they relate to autoimmune rheumatic and musculoskeletal conditions, and which inform the translation of this knowledge into advances in clinical care. Original basic, translational and clinical research is considered for publication along with results of early and late phase therapeutic trials, especially as they pertain to the underpinning science that informs clinical observations in interventional studies.