A disintegrin and metalloprotease-17 and galectin-9 are important regulators of local 4-1BB activity and disease outcome in rheumatoid arthritis
A disintegrin and metalloprotease-17 and galectin-9 are important regulators of local 4-1BB activity and disease outcome in rheumatoid arthritis
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DOI：
10.1093/rheumatology/kew237
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发表时间：
2016-10-01
期刊：
影响因子：
5.5
通讯作者：
Deleuran, Bent
中科院分区：
文献类型：
--
作者：
Nielsen, Morten Aagaard;Andersen, Thomas;Deleuran, Bent
objective.共刺激性T细胞因子在RA的进展中起重要作用。本研究探讨了4 - 1BB，解整合素和金属蛋白酶-17（ADAM-17）和半乳糖凝集素-9（Gal-9）在RA中的相互作用。将来自慢性RA患者（n = 12）的刺激的单核细胞与金属蛋白酶组织抑制剂、4 - 1BB配体和Gal-9共孵育。在新诊断的、未经治疗的RA患者（n = 97）中检查血浆样品的可溶性4 - 1BB（s4 - 1BB）。采用28个关节DAS和CRP（28DAS-CRP）、Sharp总评分、侵蚀评分和关节间隙狭窄程度评价治疗效果。RA滑膜中CD4（+）和CD8（+）T细胞表达高水平的4 - 1BB。向培养的滑膜单核细胞中加入TNF-α增加了4 - 1BB的脱落。4 - 1BB配体与Gal-9组合仅增加TNF-α脱落。RNA干扰介导的ADAM17敲低或加入ADAM17抑制剂减少了4 - 1BB脱落。4 - 1BB的脱落不受Gal-9的影响。血浆s4 - 1BB水平在早期RA中升高，并与基线时肿胀关节的数量相关。治疗3个月后，血浆s4 - 1BB水平与对照组相当。基线血浆s4 - 1BB水平与治疗2年后的DAS 28-CRP呈负相关，但与总Sharp评分、糜烂评分或关节间隙狭窄无关。在RA中，ADAM 17诱导4 - 1BB脱落。Gal-9对于4 - 1BB的功能和TNF-α的诱导是关键的。此外，高血浆s4 - 1BB水平与关节肿胀数量相关，但也与早期RA治疗2年后的低DAS 28-CRP相关。
Objective. Co-stimulatory T cell cytokines are important in the progression of RA. This study investigates the interplay between 4-1BB, a disintegrin and metalloprotease-17 (ADAM17) and galectin-9 (Gal-9) in RA.Methods. Stimulated mononuclear cells from patients with chronic RA (n = 12) were co-incubated with tissue inhibitor of metalloproteinase, 4-1BB ligand and Gal-9. Plasma samples were examined for soluble 4-1BB (s4-1BB) in newly diagnosed, treatment-na < ve patients with RA (n = 97). The 28-joint DAS with CRP (28DAS-CRP), total Sharp score, erosion score and joint space narrowing were used to evaluate treatment outcome serially over a 2-year period.Results. RA CD4(+) and CD8(+) synovial T cells express high levels of 4-1BB. The addition of TNF-alpha to cultured synovial mononuclear cells increased shedding of 4-1BB. 4-1BB ligand only increased TNF-alpha shedding in combination with Gal-9. RNA interference-mediated knockdown of ADAM17 or the addition of an ADAM17 inhibitor reduced the 4-1BB shedding. Shedding of 4-1BB was not influenced by Gal-9. Plasma levels of s4-1BB were increased in early RA and correlated with the number of swollen joints at baseline. After 3 months of treatment, the plasma levels of s4-1BB were equal to those of the controls. Baseline plasma levels of s4-1BB were inversely correlated with DAS28-CRP after 2 years of treatment, but not with total Sharp score, erosion score or joint space narrowing.Conclusion. ADAM17 induces 4-1BB shedding in RA. Gal-9 is pivotal for the function of 4-1BB and induction of TNF-alpha. Furthermore, high plasma levels of s4-1BB were associated with the number of swollen joints, but also with a low DAS28-CRP after 2 years treatment in early RA.