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.

The International Society for Bipolar Disorders Task Force report on pediatric bipolar disorder: Knowledge to date and directions for future research

“…The first study (18 BD patients, 13 major depressive disorder [MDD] patients and 20 HCs) found significantly higher levels of nuclear factor kappa beta (NF-κβ) in peripheral blood mononuclear cells, monocytes, and lymphocytes, higher IL-1β plasma levels, and greater TNF-α-induced elevations in NF-κβ in adolescents with mood disorders than in HCs. 241 The second study (40 BD patients and 20 HCs) found elevated IL-6 and TNF-α levels among adolescents with PBD. 242 …”

Tumor necrosis factor receptor 2: A potential target for antidepressant drug development

“…When considering the potential role of TNFR2 in mood disorders, it is also notable that several pathways activated during transmembrane TNFR2 forward signaling have been implicated in mood disorder pathology, including mitogen‐activated protein kinase, PI3K/Akt and NF‐κB signaling . For instance, mitogen‐activated protein kinase blockade induces depressive symptoms in rats and inhibits the antidepressant effects of ketamine .…”

“…For instance, mitogen‐activated protein kinase blockade induces depressive symptoms in rats and inhibits the antidepressant effects of ketamine . Elevated NF‐κB activity has been implicated in bipolar disorder, with adolescent bipolar disorder patients showing increased NF‐κB activation in peripheral blood and immune cells, compared with healthy control individuals . Furthermore, recombinant human TNF administration induces greater increases in NF‐κB levels in adolescent mood disorder patients, compared with controls, with NF‐κB elevations associated with exacerbation of depressive symptoms .…”

“…When considering the potential role of TNFR2 in mood disorders, it is also notable that several pathways activated during transmembrane TNFR2 forward signaling have been implicated in mood disorder pathology, including mitogen-activated protein kinase, 79,80 PI3K/Akt 81 and NF-jB signaling. 82,83 For instance, mitogen-activated protein kinase blockade induces depressive symptoms in rats and inhibits the antidepressant effects of ketamine. 80 Elevated NF-jB activity has been implicated in bipolar disorder, 83 with adolescent bipolar disorder patients showing increased NF-jB activation in peripheral blood and immune cells, compared with healthy control individuals.…”

Reducing Neuroinflammation in Psychiatric Disorders: Novel Target of Phosphodiesterase 4 (PDE4) and Developing of the PDE4 Inhibitors

“…The pathophysiology of BD is yet to be well understood, while recent studies have indicated that abnormal immunological functions may be a contributing factor [38][39][40][41][42]. Recently, positron emission tomography (PET) studies have shown microglial overactivation in the brain of patients with various psychiatric disorders [43][44][45]; [9] including bipolar disorder [42].…”