title: Early activation of p38 mitogen activated protein kinase is associated with interferon-alpha-induced depression and fatigue.
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 h for 12 h 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.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30322, United States.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Felger
authors.forename: Oyetunde
authors.initials: O
authors.lastname: Alagbe
authors.forename: Thaddeus W W
authors.initials: TW
authors.lastname: Pace
authors.forename: Bobbi J
authors.initials: BJ
authors.lastname: Woolwine
authors.forename: Fang
authors.initials: F
authors.lastname: Hu
authors.forename: Charles L
authors.initials: CL
authors.lastname: Raison
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Miller
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use; D003863:Depression / Q000139:chemically induced* / Q000201:enzymology; D004359:Drug Therapy, Combination; D005221:Fatigue / Q000139:chemically induced* / Q000201:enzymology; D019698:Hepatitis C, Chronic / Q000188:drug therapy; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000378:metabolism; D007113:Immunity, Innate; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D015850:Interleukin-6 / Q000097:blood; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D012254:Ribavirin / Q000008:administration & dosage / Q000627:therapeutic use; D012720:Severity of Illness Index; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000998:Antiviral Agents; C508600:IL6 protein, human; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D015850:Interleukin-6; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; D048051:p38 Mitogen-Activated Protein Kinases; C417083:peginterferon alfa-2b; C100416:peginterferon alfa-2a; D006854:Hydrocortisone