Inhibition of tumour necrosis factor and IL-17 production by leflunomide involves the JAK/STAT pathway.
Inhibition of tumour necrosis factor and IL-17 production by leflunomide involves the JAK/STAT pathway.
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DOI：
10.1136/ard.2008.096743
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发表时间：
2009-10
影响因子：
27.4
通讯作者：
Sánchez-Madrid F
中科院分区：
文献类型：
--
作者：
González-Alvaro I;Ortiz AM;Domínguez-Jiménez C;Aragón-Bodi A;Díaz Sánchez B;Sánchez-Madrid F
研究不同的疾病缓解抗风湿药物（DMARD）对IL-15激活的淋巴细胞介导的不同事件的影响。从健康供体分离外周血淋巴细胞（PBL），并在暴露于不同的DMARD后用IL-15活化：来氟米特、环孢菌素A、甲氨蝶呤、霉酚酸、FK-506、柳氮磺胺吡啶和金硫代苹果酸钠。然后通过流式细胞术测定PBL上不同表面分子的表达。还将细胞与单核细胞系THP-1共培养，24小时后使用免疫酶测定法测量上清液中的肿瘤坏死因子（TNF）浓度。还研究了上述药物对IL-15激活的PBL产生IL-17的影响。用来氟米特、环孢素A和FK-506处理PBL可抑制IL-15诱导的PBL表达CD 54和CD 69，以及活化PBL和THP-1细胞共培养物中TNF的产生。PBL中CD 54和CD 69的下调与TNF的产生受到抑制有关。同样，来氟米特，环孢素A和FK-506都抑制IL-15激活的PBL中IL-17的产生。有趣的是，培养基中尿苷的存在并不能逆转来氟米特的作用。此外，来氟米特在体外抑制STAT 6的磷酸化。JAK/STAT通路的抑制可能代表了来氟米特在慢性多关节炎中的额外作用，因为它损害了控制促炎性TNF和IL-17细胞因子产生的某些事件。
To study the effects of different disease-modifying antirheumatic drugs (DMARD) on different events mediated by IL-15-activated lymphocytes. Peripheral blood lymphocytes (PBL) were isolated from healthy donors and activated with IL-15 after exposure to different DMARD: leflunomide, cyclosporin A, methotrexate, mycophenolic acid, FK-506, sulphasalazine and sodium aurothiomalate. The expression of different surface molecules on the PBL was then determined by flow cytometry. Cells were also co-cultured with the monocytic cell line THP-1 and the tumour necrosis factor (TNF) concentration in the supernatant was measured after 24 h using an immunoenzyme assay. The effect of the aforementioned drugs on IL-17 production by IL-15-activated PBL was also studied. Treatment of PBL with leflunomide, cyclosporin A and FK-506 inhibited the IL-15-induced expression of both CD54 and CD69 by PBL, as well as TNF production in co-cultures of activated PBL and THP-1 cells. The downregulation of CD54 and CD69 in PBL was correlated with the inhibition of TNF production. Likewise, leflunomide, cyclosporin A and FK-506 all inhibited IL-17 production in IL-15-activated PBL. Interestingly, the effect of leflunomide was not reverted by the presence of uridine in the medium. In addition, leflunomide inhibited the phosphorylation of STAT6 in vitro. Inhibition of the JAK/STAT pathway may represent an additional effect of leflunomide in chronic polyarthritis because it impairs certain events that control proinflammatory TNF and IL-17 cytokine production.
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影响因子：
5.5
作者：
Burger, D;Begué-Pastor, N;Dayer, JM
通讯作者：
Dayer, JM
影响因子：
82.9
作者：
McInnes, IB;Leung, BP;Liew, FY
通讯作者：
Liew, FY
影响因子：
5.4
作者：
Sebbag, M;Parry, SL;Feldmann, M
通讯作者：
Feldmann, M
影响因子：
4.9
作者：
Palmer, G;Burger, D;Guerne, PA
通讯作者：
Guerne, PA
影响因子：
4.4
作者：
Miranda-Carús, ME;Balsa, A;Martín-Mola, E
通讯作者：
Martín-Mola, E