Tumor Necrosis Factor α Blockade Exacerbates Murine Psoriasis-like Disease by Enhancing Th17 Function and Decreasing Expansion of Treg Cells
Tumor Necrosis Factor α Blockade Exacerbates Murine Psoriasis-like Disease by Enhancing Th17 Function and Decreasing Expansion of Treg Cells
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DOI：
10.1002/art.27203
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发表时间：
2010-02-01
影响因子：
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通讯作者：
Young, Deborah A.
中科院分区：
文献类型：
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作者：
Ma, Hak-Ling;Napierata, Lee;Young, Deborah A.
Objective.银屑病和银屑病关节炎患者一般对肿瘤坏死因子α（TNF α）阻滞剂反应良好;然而，现在有越来越多的证据表明，一小群接受TNF α阻滞剂的类风湿性关节炎患者发生银屑病。本研究旨在探讨TNF α阻断剂诱导银屑病样皮肤病小鼠皮肤炎症加重的机制。BALB/c scid/scid小鼠接受来自供体小鼠的CD 4 + CD 45 RB（high）CD 25-（naive CD 4）T细胞后，诱导皮肤炎症。用抗白细胞介素-12（抗IL-12）/23 p40抗体或鼠TNFRII-Fc融合蛋白处理这些小鼠，并检查疾病体征，包括组织学特征、血清中的各种细胞因子水平以及受影响皮肤和引流淋巴结（LN）细胞中的细胞因子或FoxP 3转录物。在另一项研究中，在TNF α存在或不存在的情况下，用抗CD 3/ 28磁珠和适当的细胞因子将初始CD 4 + T细胞分化为Th 1或Th 17谱系。细胞因子基因表达从这些分化的细胞也被确定。TNF α的中和加剧了皮肤炎症，并显著增强了促炎细胞因子IL-1 β、IL-6、IL-17、IL-21和IL-22的表达，但抑制了皮肤中的FoxP 3表达，并减少了引流LN中FoxP 3阳性Treg细胞的数量。TNF α在初始T细胞的启动和再活化过程中也表现出不同的作用。这些结果揭示了TNF α在某些个体中对Th 17和Treg细胞的新型免疫调节作用，这可能是某些接受抗TNF治疗的患者皮肤炎症加剧的原因。
Objective. Patients with psoriasis and psoriatic arthritis respond well to tumor necrosis factor alpha (TNF alpha) blockers in general; however, there is now mounting evidence that a small cohort of patients with rheumatoid arthritis who receive TNF alpha blockers develop psoriasis. This study was undertaken to explore the mechanisms underlying TNF alpha blockade-induced exacerbation of skin inflammation in murine psoriasis-like skin disease.Methods. Skin inflammation was induced in BALB/c scid/scid mice after they received CD4+ CD45RB(high)CD25- (naive CD4) T cells from donor mice. These mice were treated with either anti interleukin- 12 (anti-IL-12)/23p40 antibody or murine TNFRII-Fc fusion protein and were examined for signs of disease, including histologic features, various cytokine levels in the serum, and cytokine or FoxP3 transcripts in the affected skin and draining lymph node (LN) cells. In a separate study, naive CD4+ T cells were differentiated into Th1 or Th17 lineages with antiCD3/ 28 magnetic beads and appropriate cytokines in the presence or absence of TNF alpha. Cytokine gene expression from these differentiated cells was also determined.Results. Neutralization of TNF alpha exacerbated skin inflammation and markedly enhanced the expression of the proinflammatory cytokines IL-1 beta, IL-6, IL-17, IL-21, and IL-22 but suppressed FoxP3 expression in the skin and reduced the number of FoxP3-positive Treg cells in the draining LNs. TNF alpha also demonstrated a divergent role during priming and reactivation of naive T cells.Conclusion. These results reveal a novel immunoregulatory role of TNF alpha on Th17 and Treg cells in some individuals, which may account for the exacerbation of skin inflammation in some patients who receive anti-TNF treatments.