Cytokines and glucocorticoid receptor signaling. Relevance to major depression

Abstract

Data suggest that the activation of immune responses and the release of inflammatory cytokines may play a role in the pathophysiology of major depression. One mechanism by which cytokines may contribute to depression is through their effects on the glucocorticoid receptor (GR). Altered GR function in depression has been demonstrated by neuroendocrine challenge tests that reliably reveal reduced GR sensitivity as manifested by nonsuppression of cortisol following dexamethasone administration in vivo and lack of immune suppression following administration of glucocorticoids in vitro. Relevant to the GR, cytokines have been shown to decrease GR expression, block translocation of the GR from cytoplasm to nucleus, and disrupt GR-DNA binding through nuclear protein-protein interactions. In addition, cytokines have been shown to increase the expression of the relatively inert GR beta isoform. Specific cytokine signaling molecules that have been shown to be involved in the disruption of GR activity include p38 mitogen-activated protein kinase, which is associated with reduced GR translocation, and signal transducer and activator of transcription (STAT)5, which binds to GR in the nucleus. Nuclear factor-kappaB (NF-kappaB) also has been shown to lead to GR suppression through mutually inhibitory GR-NF-kappaB nuclear interactions. Interestingly, several antidepressants have been shown to enhance GR function, as has activation of protein kinase A (PKA). Antidepressants and PKA activation have also been found to inhibit inflammatory cytokines and their signaling pathways, suggesting that drugs that target both inflammatory responses and the GR may have special efficacy in the treatment of depression.

Figure 1

Baseline and stress-induced inflammatory responses in patients with major depression. Patients with major depression and a history of increased early life stress displayed elevated baseline and acute psychosocial stress-induced circulating concentrations of interleukin (IL)-6, as well as enhanced psychosocial stress-induced nuclear factor-κB (NF-κB)-DNA binding in peripheral blood mononuclear cells. Left panel: Circulating concentrations of IL-6 before and 30, 60, 75, and 90 min after the start of the Trier Social Stressor Test (TSST) in healthy controls vs. patients with current major depression and increased history of early life stress. ^* vs. Control group at the given timepoint, P ≤ 0.05; ⁺ vs. 0 min within the same group P < 0.025. Right panel: Percent change in nuclear NF-κB-DNA binding from before to 30 min after the start of the TSST (ΔNF-κB) in a subset of the same participants. ^* vs. control group, P ≤ 0.05. (Reprinted with permission from Pace, T. W. W., Mletzko, T.C., Alagbe, O., Musselman, D.L., Nemeroff, C.B., Miller, A.H., 2006. Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. American Journal of Psychiatry 163, 1630–1633, Copyright 2006 American Psychiatric Publishing, Inc.)

Figure 2

Interactions between cytokine and glucocorticoid receptor (GR) signaling pathways. Selected cytokines and their signal transduction pathways are depicted in a simplified fashion to illustrate representative interactions between cytokine and GR signaling events. Cortisol binds to GR, resulting in dissociation of heat shock protein (HSP) complexes and subsequent phosphorylation. GR then translocates to the nucleus, where it dimerizes and either interacts with other transcription factors or binds to glucocorticoid response elements (GREs) upstream of GR-regulated genes (e.g., inhibitor κ-B or IκB). TNF-α binds to its receptor and results in activation of IκB kinase β (IKKβ), which phosphorylates IκB, allowing NF-κB (shown here as p65 and p50 Rel subunits) to translocate to the nucleus. Through protein-protein interactions, activated NF-κB associates with GR, thus interfering with GR-DNA binding. IL-1 binds to its receptor, initiating (a) mitogen activated protein kinase (MAPK) kinase (MKK)4/7, which culminates in activation of c-Jun amino-terminal kinase (JNK), (b) MKK3/6, which culminates in activation of p38, and (c) Ras, which results in activation of the extracellular signal-related kinase (Erk)1/2. Of note, MKK4/7 activation of JNK can also occur through TNF-α receptor binding. As depicted by the dotted lines, both p38 and JNK can phosphorylate key GR residues, thereby disrupting nuclear translocation of GR. Interferon (IFN)-α binds to its receptor resulting in Janus kinase (Jak) phosphorylation, represented as Jak1 and tyrosine kinase (Tyk)2. Jak1 phosphorylates signal transducers and activators of transcription (STAT) proteins, including STAT1, STAT3, and STAT5. Tyk2 can also activate elements of the Ras signaling pathway, resulting in activation of Erk1/2. Activated STATs translocate to the nucleus, where they can interact with GR through protein-protein interactions, thereby interfering with GR-DNA binding. Phospholipids are hydrolyzed by phospholipase A2 (PLA2) to form arachidonic acid, which is metabolized by cyclooxygenase (COX) 2 to produce prostaglandin D2 (PGD2). Stimulation of serotonergic receptors 4, 6, or 7 (5-HT4, 6, 7) and beta adrenergic receptors (beta1) induces a conformational change in G stimulatory (Gs) protein, which then activates adenylyl cyclase (AC). AC, in turn, converts adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). cAMP then induces a conformational change in protein kinase A (PKA), which translocates to the nucleus, where it is able to enhance GR-DNA binding. In addition, the catalytic subunit of PKA (PKAc) interacts with p65, thereby inhibiting NF-κB nuclear translocation. (Reprinted with permission from Pace, T. W. W., Hu, F., & Miller, A. H. Cytokine-effects on glucocorticoid receptor function: relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression. Brain, Behavior, and Immunity 21, 9–19, Copyright 2007 Elsevier.) (In color in Annals online.)

Figure 3

Glucocorticoid and inflammatory signaling during chronic stress. Compared to controls, peripheral blood monocytes isolated from subjects exposed to chronic caregiving stress exhibited significant increases in expression of genes containing promoter response elements for NF-κB (A) and significant decreases in genes containing promoter elements for the GR (B). Chronic caregivers also exhibited significant increases in plasma concentrations of IL-1ra (C), as well as increased plasma concentrations of C-reactive protein (D). (Reprinted with permission from Miller, G. E., Chen, E., Sze, J., Marin, T., Arevalo, J.M., Doll, R., Ma, R., and Cole, S.W. A functional genomic fingerprint of chronic stress in humans: blunted glucocorticoid and increased NF-κB signaling. Biological Psychiatry. 64(4), 266–272, Copyright 2008 Elsevier.)

Figure 4

Diurnal cortisol secretion during treatment with IFN-α. Patients who received interferon (IFN)-α treatment for 12 weeks exhibited significant flattening of the cortisol curve compared to non-IFN-α-treated controls. Mean raw cortisol values from 9 a.m. to 9 p.m. in controls (blue/solid line) versus subjects treated with IFN-α plus ribavirin (red/dashed line) at Visit 1 and Visit 2. Cortisol slopes from 9 a.m. to 9 p.m. in controls (blue/solid line) versus subjects treated with IFN-α plus ribavirin (red/dashed line) at Visit 1 and Visit 2 are also depicted in inserts in each graph. Compared to control subjects, IFN-α/ribavirin-treated patients exhibited a significantly flatter cortisol slope (P < 0.05) and significantly higher evening cortisol values (P < 0.05). (Reprinted with permission from Raison, C.L., Borisov, A.S., Woolwine, B.J., Massung, B., Vogt, G., and Miller, A.H. Interferon-alpha effects on diurnal hypothalamic-pituitary-adrenal axis activity: relationship with proinflammatory cytokines and behavior. Molecular Psychiatry. 3 June 2008, doi:10.1038/mp.2008.58, Copyright 2008 Nature Publishing Group.) (In color in Annals online.)