Early activation of p38 mitogen activated protein kinase is associated with interferon-alpha-induced depression and fatigue.
Early activation of p38 mitogen activated protein kinase is associated with interferon-alpha-induced depression and fatigue.
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DOI：
10.1016/j.bbi.2011.02.015
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发表时间：
2011-08
影响因子：
15.1
通讯作者：
Miller, Andrew H.
中科院分区：
文献类型：
--
作者：
Felger, Jennifer C.;Alagbe, Oyetunde;Pace, Thaddeus W. W.;Woolwine, Bobbi J.;Hu, Fang;Raison, Charles L.;Miller, Andrew H.
关键词：
细胞因子诱导的p38丝裂原活化蛋白激酶（MAPK）的刺激已被证明影响行为相关的病理生理途径，包括单胺神经传递和神经内分泌功能，因此可能有助于在慢性给药天然免疫细胞因子干扰素(IFN)- α时发生的行为改变。因此，在本研究中，11例慢性丙型肝炎患者在初始注射ifn - α后的12小时内，每2小时通过流式细胞术分析外周血淋巴细胞中细胞内p38 MAPK的磷酸化（激活）。每小时评估血浆促肾上腺皮质激素、皮质醇和白细胞介素-6的浓度。在基线和ifn - α治疗4周和12周后测量抑郁和疲劳症状。急性给予ifn - α显著增加细胞内磷酸化p38 （p-p38）染色阳性的淋巴细胞百分比。在ifn - α治疗的前12周，出现临床显著抑郁症状（Montgomery Asberg抑郁评定量表（MADRS）评分≥15）的患者中，ifn - α诱导的p-p38升高明显更大。第一次注射ifn - α后p-p38阳性淋巴细胞百分比的增加也与第4周和第12周的抑郁严重程度高度相关（r=0.85, p=0.001）。疲劳也有类似的关系。对p-p38诱导与先前报道的预测ifn - α诱导的抑郁症状的因素之间关系的检查显示，p-p38与基线MADRS （r=0.82, p=0.002）和初始注射ifn - α时的皮质醇反应（r=0.91, p=0.000）有很强的相关性。综上所述，这些发现表明p38 MAPK信号通路对免疫刺激的敏感性与慢性ifn - α治疗期间的抑郁症状有关。
Cytokine-induced stimulation of p38 mitogen activated protein kinase (MAPK) has been shown to influence behaviorally-relevant pathophysiologic pathways including monoamine neurotransmission and neuroendocrine function and thus may contribute to behavioral changes that occur during chronic administration of the innate immune cytokine, interferon (IFN)-alpha. Accordingly, in the current study, phosphorylation (activation) of intracellular p38 MAPK in peripheral blood lymphocytes was analyzed by flow cytometry every 2 hours for 12 hours following the initial injection of IFN-alpha in eleven patients with chronic hepatitis C. Hourly assessments of plasma concentrations of adrenocorticotropic hormone, cortisol and interleukin-6 were also obtained. Symptoms of depression and fatigue were measured at baseline and after 4 and 12 weeks of IFN-alpha treatment. Acute administration of IFN-alpha significantly increased the percentage of lymphocytes staining positive for intracellular phosphorylated p38 (p-p38). IFN-alpha-induced increases in p-p38 were significantly greater in patients that developed clinically significant depressive symptoms [Montgomery Asberg Depression Rating Scale (MADRS) score ≥15] during the first 12 weeks of IFN-alpha treatment. Increases in the percentage of p-p38-positive lymphocytes following the first IFN-alpha injection also highly correlated with depression severity at weeks 4 (r=0.85, p=0.001) and 12 (r=0.70, p=0.018). Similar relationships were observed for fatigue. Examination of relationships between p-p38 induction and factors previously reported to predict IFN-alpha-induced depressive symptoms revealed strong associations of p-p38 with baseline MADRS (r=0.82, p=0.002) and cortisol responses to the initial injection of IFN-alpha (r=0.91, p=0.000). Taken together, these findings indicate that sensitivity of p38 MAPK signaling pathways to immune stimulation is associated with depressive symptoms during chronic IFN-alpha treatment.
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