Srivastava M D
Department of Pediatrics, MetroHealth Medical Center, Cleveland, Ohio 44109, USA.
Res Commun Mol Pathol Pharmacol. 2001 Jul;109(1-2):125-41.
Designer drug etanercept (TNFR:Fc) is an inhibitor of TNF-alpha that binds with greater affinity than membrane receptors. Its full immunomodulatory effects are unknown. Approved for rheumatoid arthritis, its therapeutic potential in Crohn's disease has yet to be explored. We describe the course of a steroid-dependent patient with Crohn's disease given etanercept, and its effects on cytokine protein and mRNA expression and transcription factor activity in human leukocytes. Etanercept 25 mg s.c., was given twice weekly for 1 month. Weekly ESR, disease activity index, prednisone requirement, and serum cytokines were determined. In vitro, effects of physiologic concentrations of etanercept on cytokine protein and mRNA, and NFKB and GR transcription factor activity, were determined using MOT and U937 cell lines and peripheral blood mononuclear cells. Rapid clinical, biochemical, and immunologic improvement occurred, but obstruction due to stricture developed after 4 weeks. In vitro, constitutive and stimulated production of TNF-beta, IL-1beta, MIP-1beta, and IL-8 by normal mononuclear cells declined with etanercept, detectable TNF-alpha increased. MOT TNF-alpha expression tripled, mRNA for IL-12 p40 doubled, GR activity declined in U937 cells, NFKB was unaffected. Etanercept has complex immunomodulatory effects, and may be useful in Crohn's disease, but acutely decreased inflammation could worsen stricture.
设计药物依那西普（TNFR:Fc）是一种肿瘤坏死因子-α（TNF-α）抑制剂，其与TNF-α的结合亲和力高于膜受体。其完整的免疫调节作用尚不清楚。依那西普已被批准用于治疗类风湿性关节炎，但其在克罗恩病中的治疗潜力尚未得到探索。我们描述了一名依赖类固醇的克罗恩病患者接受依那西普治疗的过程，以及该药物对人白细胞中细胞因子蛋白、mRNA表达和转录因子活性的影响。皮下注射依那西普25mg，每周两次，共1个月。每周测定红细胞沉降率、疾病活动指数、泼尼松需求量和血清细胞因子。在体外，使用MOT和U937细胞系以及外周血单核细胞，测定生理浓度的依那西普对细胞因子蛋白、mRNA以及核因子κB（NFKB）和糖皮质激素受体（GR）转录因子活性的影响。患者出现了快速的临床、生化和免疫改善，但4周后因狭窄导致肠梗阻。在体外，正常单核细胞组成性和刺激性产生的肿瘤坏死因子-β（TNF-β）、白细胞介素-1β（IL-1β）、巨噬细胞炎性蛋白-1β（MIP-1β）和白细胞介素-8（IL-8）随依那西普而下降，可检测到的TNF-α增加。MOT细胞中TNF-α表达增加两倍，白细胞介素-12 p40的mRNA增加一倍，U937细胞中的GR活性下降，NFKB未受影响。依那西普具有复杂的免疫调节作用，可能对克罗恩病有用，但急性炎症减轻可能会使狭窄恶化。
