Inflammatory cytokines and nuclear factor-kappa B activation in adolescents with bipolar and major depressive disorders

Abstract

Adults with bipolar disorder (BD) and major depressive disorder (MDD) have higher circulating levels of proinflammatory cytokines than healthy controls. However, it is not known whether pediatric-onset patients with BD or MDD show increases in levels of inflammation or activation of nuclear factor kappa B (NF-κB), a key transcription factor in inflammatory signaling. Circulating levels of inflammatory cytokines, as well as spontaneous and stimulated levels of activated NF-κB in total peripheral blood mononuclear cells, monocytes and lymphocytes were measured in adolescents with BD (n=18), MDD (n=13), or no psychiatric history (n=20). Participants had a range of mood symptoms at time of testing. Adolescents with BD had significantly higher spontaneous levels of NF-κB in peripheral blood mononuclear cells, monocyte and lymphocyte populations, and higher plasma levels of IL-1β than healthy controls. Following stimulation with recombinant human TNF-α, participants with BD and MDD both had greater increases in NF-κB in monocytes than controls. Further, greater stimulated increases of NF-κB in monocytes were associated with the current severity of depressive symptoms. The results are limited by the small sample and cross-sectional design. Interventions that target early immunological dysregulation should be examined in relation to long-term outcomes in youth with bipolar and depressive disorders.

Clinical trial registration information: Early Intervention for Youth at Risk for Bipolar Disorder, https://ichgcp.net/clinical-trials-registry/NCT01483391.

Keywords: Inflammation; Inflammatory signaling; Interleukin-1; Lymphocytes; Monocytes; NF-ΚB; Peripheral blood mononuclear cells.

Conflict of interest statement

Conflict of Interest

Dr. Miklowitz has received research funding from the National Institute of Mental Health, the UCLA Cousins Center for Psychoneuroimmunology, the Deutsch, Kayne, and Knapp Family Foundations, Danny Alberts Foundation, Attias Family Foundation, and the American Foundation for Suicide Prevention; and book royalties from Guilford Press and John Wiley and Sons. Dr. Irwin is supported by the NIMH, the UCLA Cousins Center for Psychoneuroimmunology; and the UCLA Claude D. Pepper Older Americans Independence Center. Dr. Breen is supported by the UCLA Cousins Center for Psychoneuroimmunology and the UCLA Claude D. Pepper Older Americans Independence Center. Dr. Eisenberger is supported by the NIMH, the National Institute on Drug Abuse, and the National Alliance for Research on Schizophrenia and Depression. The other authors report no financial relationships with commercial interests.

Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Figures

Fig. 1

Interleukin -1β (IL-1β) Levels in Adolescents with Bipolar Disorder, Major Depressive Disorder (MDD), or No Psychiatric History (Controls). Note. Mean IL-1β levels + standard errors, adjusted for Body Mass Index, are pictured. Plasma levels of IL-1β were significantly higher in youth with BD than in controls (p = 0.03).

Fig. 2

Spontaneous (Unstimulated) Nuclear Factor-Kappa B (NF-κB) Levels in Adolescents with Bipolar Disorder, Major Depressive Disorder (MDD), or No Psychiatric History (Controls). Notes. Values are mean (+ standard error) fluorescence intensity scores expressing amount of NF-κB signaling in monocyte, lymphocyte and total peripheral blood mononuclear cell (PBMC) populations. Spontaneous levels of NF-κB in monocytes, lymphocytes, and total peripheral blood mononuclear cells were higher in bipolar youth compared to healthy controls but did not differ from levels observed in adolescents with MDD.

Fig. 3

Increases in Nuclear Factor - Kappa B (NF-κB) Activation following TNF-alpha Stimulation in Adolescents with Bipolar Disorder, Major Depressive Disorder (MDD), or No Psychiatric History (Controls). Notes. MDD = Major Depressive Disorder; PBMC= Peripheral Blood Mononuclear Cells. Values are mean (+ standard error) changes in fluorescence intensity scores (stimulated MFI - unstimulated MFI) in monocyte, lymphocyte and total peripheral blood mononuclear cell populations. The bipolar and MDD groups both had greater increases in stimulated monocyte levels than controls (p