Early activation of p38 mitogen activated protein kinase is associated with interferon-alpha-induced depression and fatigue

• Type of Material: Article
• Authors: Jennifer Felger, Emory University; Oyetunde Alagbe, Newport Integrated Behavioral Hospital Inc.; Thaddeus Pace, Emory University; Bobbi J. Woolwine, Emory University; Fang Hua, Emory University; Charles L Raison, Emory University; Andrew H Miller, Emory University
• Language: English
• Date: 2011-08
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2011, Elsevier
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bbi.2011.02.015
• Title of Journal or Parent Work: Brain, Behavior, and Immunity
• ISSN: 0889-1591
• Volume: 25
• Issue: 6
• Start Page: 1094
• End Page: 1098
• Grant/Funding Information: This study was supported in part by grants from the National Institutes of Health to CLR (K23 MH064619, R01 MH070553) and AHM (K05 MH069124, R01 HL073921, MHR01MH075102, T32 MH020018) as well as the Emory Center for AIDS Research (P30 AI050409) and the Flow Cytometry Core Facility of the Emory University School of Medicine.; In addition, the study was supported by PHS Grant UL1 RR025008 from the Clinical and Translational Science Award program and PHS Grant M01 RR0039 from the General Clinical Research Center program, National Institutes of Health, National Center for Research Resources.; Andrew H. Miller has received research support from Centocor Inc., GlaxoSmithKline, and Schering-Plough Research Institute
• Keywords: innate immunity; interferon-alpha; flow cytometry; fatigue; p38 mitogen activated protein kinase; cytokines; cortisol; depression
• Research Categories: Health Sciences, Immunology; Psychology, Behavioral

Abstract

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.