Attenuation of murine collagen-induced arthritis by a novel, potent, selective small molecule inhibitor of IκB kinase 2, TPCA-1 (2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide), occurs via reduction of proinflammatory cytokines and antigen-induced T cell proliferation
Attenuation of murine collagen-induced arthritis by a novel, potent, selective small molecule inhibitor of IκB kinase 2, TPCA-1 (2-[(aminocarbonyl)amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide), occurs via reduction of proinflammatory cytokines and antigen-induced T cell proliferation
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DOI：
10.1124/jpet.104.074484
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发表时间：
2005-01-01
影响因子：
3.5
通讯作者：
Roshak, AK
中科院分区：
文献类型：
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作者：
Podolin, PL;Callahan, JF;Roshak, AK
IKK-2激酶（IKK-2）在核因子- kappab通过刺激如肿瘤坏死因子(TNF)- α和白细胞介素(IL)-1调节促炎分子的产生中起关键作用，这表明抑制IKK-2可能对类风湿关节炎的治疗有益。在本研究中，我们证明了一种新的、有效的（IC50 = 17.9 nM）、选择性的人ikk - 2,2 -[（氨基羰基）氨基]-5-（4-氟苯基）3-硫代苯甲酰胺（TPCA-1）抑制剂，抑制脂多糖诱导的人单核细胞产生tnf - α、IL-6和IL-8， IC50 = 170至320 nM。预防性给药3、10或20 mg/kg的TPCA-1（每日1次、每日1次）可导致小鼠胶原诱导关节炎（CIA）严重程度的剂量依赖性降低。以10mg /kg，腹腔注射tpa -1导致的疾病严重程度的显著降低和疾病发作的延迟，与每隔一天预防性给予抗风湿药依那西普（4mg /kg，腹腔注射，每隔一天）的效果相当。p65的核定位以及il -1 β、IL-6、tnf - α和干扰素- γ的水平在TPCA-1-和依那西普治疗的小鼠爪组织中显著降低。此外，体内给药TPCA-1可显著降低胶原诱导的T细胞体外增殖。治疗性给予tpa -1 20 mg/kg，而不是3或10 mg/kg，每日一次，每日一次，显著降低了CIA的严重程度，依那西普12.5 mg/kg，每隔一天一次，每日一次。这些结果表明，促炎介质的减少和抗原诱导的T细胞增殖的抑制是IKK-2抑制剂TPCA-1抑制CIA的机制。
Demonstration that IkappaB kinase 2 (IKK-2) plays a pivotal role in the nuclear factor-kappaB-regulated production of proinflammatory molecules by stimuli such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 suggests that inhibition of IKK-2 may be beneficial in the treatment of rheumatoid arthritis. In the present study, we demonstrate that a novel, potent (IC50 = 17.9 nM), and selective inhibitor of human IKK-2, 2-[(aminocarbonyl) amino]-5-(4-fluorophenyl)3- thiophenecarboxamide (TPCA-1), inhibits lipopolysaccharide-induced human monocyte production of TNF-alpha, IL-6, and IL-8 with an IC50 = 170 to 320 nM. Prophylactic administration of TPCA-1 at 3, 10, or 20 mg/kg, i. p., b. i. d., resulted in a dose-dependent reduction in the severity of murine collagen-induced arthritis (CIA). The significantly reduced disease severity and delay of disease onset resulting from administration of TPCA-1 at 10 mg/kg, i. p., b. i. d. were comparable to the effects of the antirheumatic drug, etanercept, when administered prophylactically at 4 mg/kg, i. p., every other day. Nuclear localization of p65, as well as levels of IL-1beta, IL-6, TNF-alpha, and interferon-gamma, were significantly reduced in the paw tissue of TPCA-1- and etanercept-treated mice. In addition, administration of TPCA-1 in vivo resulted in significantly decreased collagen-induced T cell proliferation ex vivo. Therapeutic administration of TPCA-1 at 20 mg/kg, but not at 3 or 10 mg/kg, i. p., b. i. d., significantly reduced the severity of CIA, as did etanercept administration at 12.5 mg/kg, i. p., every other day. These results suggest that reduction of proinflammatory mediators and inhibition of antigen-induced T cell proliferation are mechanisms underlying the attenuation of CIA by the IKK-2 inhibitor, TPCA-1.