Max Planck Institute of Psychiatry, Munich, Germany.
Brain Behav Immun. 2013 Jul;31:205-15. doi: 10.1016/j.bbi.2013.04.004. Epub 2013 Apr 25.
The tumor necrosis factor (TNF) antagonist infliximab was recently found to reduce depressive symptoms in patients with increased baseline inflammation as reflected by a plasma C-reactive protein concentration >5 mg/L. To further explore predictors and targets of response to infliximab, differential gene expression was examined in peripheral blood mononuclear cells from infliximab responders (n=13) versus non-responders (n=14) compared to placebo at baseline and 6 h, 24 h, and 2 weeks after the first infliximab infusion. Treatment response was defined as 50% reduction in depressive symptoms at any point during the 12-week trial. One-hundred-forty-eight gene transcripts were significantly associated (1.2-fold, adjusted p≤0.01) with response to infliximab and were distinct from placebo responders. Transcripts predictive of infliximab response were associated with gluconeogenesis and cholesterol transport, and were enriched in a network regulated by hepatocyte nuclear factor (HNF)4-alpha, a transcription factor involved in gluconeogenesis and cholesterol and lipid homeostasis. Of the 148 transcripts differentially expressed at baseline, 48% were significantly regulated over time in infliximab responders, including genes related to gluconeogenesis and the HNF4-alpha network, indicating that these predictive genes were responsive to infliximab. Responders also demonstrated inhibition of genes related to apoptosis through TNF signaling at 6 h and 24 h after infusion. Transcripts down-regulated in responders 2 weeks after infliximab were related to innate immune signaling and nuclear factor-kappa B. Thus, baseline transcriptional signatures reflective of alterations in glucose and lipid metabolism predicted antidepressant response to infliximab, and infliximab response involved regulation of metabolic genes and inhibition of genes related to innate immune activation.
肿瘤坏死因子（TNF）拮抗剂英夫利昔单抗最近被发现可减轻基线炎症升高（反映为血浆 C 反应蛋白浓度>5mg/L）的患者的抑郁症状。为了进一步探索英夫利昔单抗反应的预测因子和靶点，我们比较了基线和第一次英夫利昔单抗输注后 6 小时、24 小时和 2 周时，英夫利昔单抗应答者（n=13）与无应答者（n=14）和安慰剂组的外周血单个核细胞的差异基因表达。治疗反应定义为在 12 周试验期间的任何时间点抑郁症状减轻 50%。148 个基因转录物与英夫利昔单抗的反应显著相关（1.2 倍，调整后的 p≤0.01），与安慰剂应答者不同。预测英夫利昔单抗反应的转录物与糖异生和胆固醇转运相关，并且富集在受肝细胞核因子（HNF）4-α调节的网络中，HNF4-α是参与糖异生和胆固醇及脂质稳态的转录因子。在基线时差异表达的 148 个转录物中，48%在英夫利昔单抗应答者中随时间显著调节，包括与糖异生和 HNF4-α网络相关的基因，表明这些预测基因对英夫利昔单抗有反应。应答者在输注后 6 小时和 24 小时还表现出抑制与 TNF 信号相关的凋亡基因。英夫利昔单抗 2 周后下调的转录物与先天免疫信号和核因子-κB 有关。因此，反映葡萄糖和脂质代谢变化的基线转录特征可预测英夫利昔单抗的抗抑郁反应，英夫利昔单抗反应涉及代谢基因的调节和抑制与先天免疫激活相关的基因。
