Chenna Narendra Sudeep, Chalise Jaya Prakash, Magnusson Mattias, Uppugunduri Srinivas
Autoimmunity & Immune Regulation (AIR), Department of Clinical & Experimental Medicine, Linköping University, Linköping, Sweden.
Department of Clinical Chemistry and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
PLoS One. 2015 Oct 29;10(10):e0141863. doi: 10.1371/journal.pone.0141863. eCollection 2015.
Uridine has earlier been show to down modulate inflammation in models of lung inflammation. The aim of this study was to evaluate the anti-inflammatory effect of uridine in arthritis.
Arthritis was induced by intra-articular injection of mBSA in the knee of NMRI mice pre-immunized with mBSA. Uridine was either administered locally by direct injection into the knee joint or systemically. Systemic treatment included repeated injections or implantation of a pellet continuously releasing uridine during the entire experimental procedure. Anti-mBSA specific immune responses were determined by ELISA and cell proliferation and serum cytokine levels were determined by Luminex. Immunohistochemistry was used to identify cells, study expression of cytokines and adhesion molecules in the joint.
Local administration of 25-100 mg/kg uridine at the time of arthritis onset clearly prevented development of joint inflammation. In contrast, systemic administration of uridine (max 1.5 mg uridine per day) did not prevent development of arthritis. Protection against arthritis by local administration of uridine did not affect the anti-mBSA specific immune response and did not prevent the rise in serum levels of pro-inflammatory cytokines associated with the triggering of arthritis. In contrast, local uridine treatment efficiently inhibited synovial expression of ICAM-1 and CD18, local cytokine production and recruitment of leukocytes to the synovium.
Local, but not systemic administration of uridine efficiently prevented development of antigen-induced arthritis. The protective effect did not involve alteration of systemic immunity to mBSA but clearly involved inhibition of synovial expression of adhesion molecules, decreased TNF and IL-6 production and prevention of leukocyte extravasation. Further, uridine is a small, inexpensive molecule and may thus be a new therapeutic option to treat joint inflammation in RA.
在肺部炎症模型中，尿苷已被证明能下调炎症反应。本研究的目的是评估尿苷在关节炎中的抗炎作用。
用mBSA预先免疫NMRI小鼠，然后通过膝关节内注射mBSA诱导关节炎。尿苷通过直接注射到膝关节内进行局部给药或全身给药。全身治疗包括重复注射或植入在整个实验过程中持续释放尿苷的药丸。通过酶联免疫吸附测定法（ELISA）测定抗mBSA特异性免疫反应，通过Luminex测定细胞增殖和血清细胞因子水平。免疫组织化学用于识别细胞，研究关节中细胞因子和黏附分子的表达。
在关节炎发作时局部给予25 - 100mg/kg尿苷可明显预防关节炎症的发展。相比之下，全身给予尿苷（每天最大1.5mg尿苷）不能预防关节炎的发展。局部给予尿苷对关节炎的保护作用不影响抗mBSA特异性免疫反应，也不能阻止与关节炎触发相关的促炎细胞因子血清水平的升高。相反，局部尿苷治疗可有效抑制细胞间黏附分子-1（ICAM-1）和CD18的滑膜表达、局部细胞因子产生以及白细胞向滑膜的募集。
局部而非全身给予尿苷可有效预防抗原诱导的关节炎的发展。其保护作用不涉及对mBSA的全身免疫改变，但明显涉及抑制黏附分子的滑膜表达、减少肿瘤坏死因子（TNF）和白细胞介素-6（IL-6）的产生以及防止白细胞外渗。此外，尿苷是一种小分子、廉价的分子，因此可能是治疗类风湿性关节炎（RA）关节炎症的一种新的治疗选择。
