Cai Song

Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways

It is of considerable translational importance whether depression is a form or a consequence of sickness behavior. Sickness behavior is a behavioral complex induced by infections and immune trauma and mediated by pro-inflammatory cytokines. It is an adaptive response that enhances recovery by conserving energy to combat acute inflammation. There are considerable phenomenological similarities between sickness behavior and depression, for example, behavioral inhibition, anorexia and weight loss, and melancholic (anhedonia), physio-somatic (fatigue, hyperalgesia, malaise), anxiety and neurocognitive symptoms. In clinical depression, however, a transition occurs to sensitization of immuno-inflammatory pathways, progressive damage by oxidative and nitrosative stress to lipids, proteins, and DNA, and autoimmune responses directed against self-epitopes. The latter mechanisms are the substrate of a neuroprogressive process, whereby multiple depressive episodes cause neural tissue damage and consequent functional and cognitive sequelae. Thus, shared immuno-inflammatory pathways underpin the physiology of sickness behavior and the pathophysiology of clinical depression explaining their partially overlapping phenomenology. Inflammation may provoke a Janus-faced response with a good, acute side, generating protective inflammation through sickness behavior and a bad, chronic side, for example, clinical depression, a lifelong disorder with positive feedback loops between (neuro)inflammation and (neuro)degenerative processes following less well defined triggers.

The Effects of Psychological Stress on Leukocyte Subset Distribution in Humans: Evidence of Immune Activation

The aim of the present study was to examine the effects of academic examination stress on leukocyte subset distribution in university students. Thirty-eight university students had repeated blood collections for white blood cell differentiation and flow cytometric assay of lymphocytic subsets a few weeks before and after (i.e. two baseline conditions) as well as the day before a difficult academic examination (i.e. stress condition). Flow cytometry was used to determine the number of peripheral blood mononuclear cells (PBMC). In students, who were reactors to psychological stress (criterion based on changes in the Perceived Stress Scale, PSS), but not in stress non-reactors, a significant increase in the number of neutrophils, monocytes, CD8+, CD2+CD26+, and CD2+HLA-DR+ T cells and CD19+ B cells, and significant reductions in the CD4+/CD8+ T cell ratio were observed in the stress condition. There were significant and positive relationships between the stress-induced changes in perceived stress (PSS scale) and number of leukocytes, neutrophils, CD2+, CD2+CD26+ and CD2+HLADR+ T cells, and CD19+ B cells. There were significant and negative relationships between the stress-induced changes in the CD4+/CD8+ ratio and the stress-induced changes in the PSS scale. Female students taking oral contraceptives showed significantly higher stress-induced responses in number of leukocytes, neutrophils and CD19+ B cells than male and female students without use of oral contraceptives. The results suggest that academic examination stress induces changes in the distribution of PBMC, which indicate immune activation and which are probably orchestrated by a stress-induced production of cytokines.

Targeting IL-1 in depression

Introduction: Depression is associated with inflammation, Th1 and Th17 responses, oxidative and nitrosative stress (O&NS), autoimmune responses against neoantigenic determinants, and neuroprogression (i.e., neurodegeneration, impaired plasticity and reduced neurogenesis). These pathways involve increased monocytic activation and interleukin-1 (IL-1) levels. Areas covered: This review will highlight the putative role of IL-1 in depression and the potential use of IL-1 signaling blockade as a treatment of depression. Electronic databases, i.e., Scopus, PUBMED and Google Scholar were employed using keywords: depression, depressive-like, interleukin-1, and interleukin-1 receptor antagonist (IL-1RA). Expert opinion: Ample studies show that depression is accompanied by increased levels of IL-1 and IL-1RA, which attenuates the pro-inflammatory activities of IL-1. In some, but not all studies, antidepressant treatment decreased IL-1β levels. In translational models, IL-1β administration elicits depressive-like behaviors, neuroinflammation and neuroprogression, whereas treatment with IL-1RA yields antidepressant-like effects and attenuates neuroprogression. Anakinra, an IL-1RA, targets not only IL-1 signaling, but also Th1, Th17, O&NS and neuroprogressive pathways and therefore may be advanced to clinical Phase-II trials in depression due to medical conditions associated with an elevated IL-1/IL-1RA ratio.

Dietary ethyl-eicosapentaenoic acid but not soybean oil reverses central interleukin-1-induced changes in behavior, corticosterone and immune response in rats.

Omega (n)-3 and n-6 fatty acids are important membrane components of neurons and immune cells, and related to psychiatric and inflammatory diseases. Increased ratio of n-6/n-3 in the blood has been reported in depressed patients and in students following stress exposure. The n-3 fatty acid, eicosapentaenoic acid (ethyl-EPA) suppresses inflammation and has antidepressant properties. Interleukin (IL)-1β can stimulate corticosterone secretion, induce anxiety and stress-like behavior and inflammatory responses. This study was to evaluate the effect of diets enriched with coconut oil, ethyl-EPA and soybean oil on central IL-1β induced stress and anxiety-like behavior, induced changes in the concentration of prostaglandin (PG) E2 and corticosterone and the release of IL-10. Groups of rats were fed with either 5% coconut oil (as control diet), 0.2% EPA with 4.8% coconut oil or 1% EPA with 4% coconut oil and 5% soybean oil for 7 weeks. The central administration of IL-1β induced sickness, stress and anxiety-like behavior as indicated by a reduction in body weight, decreased time spent, and the number of entries, into the open arms of the elevated plus maze and decreased exploration and entry into the central zone of the “open field” apparatus. IL-1β also increased PGE2 and corticosterone concentrations and decreased the release of IL-10 from leucocytes. Food enriched with ethyl-EPA but not soybean oil, significantly attenuated most of these changes. These results demonstrate that ethyl-EPA has anti-inflammatory, anti-stress and anti-anxiety effects in rats.

In vitro immunoregulatory effects of lithium in healthy volunteers

Rationale: There is now some evidence that major depression is associated with activation of the inflammatory response system (IRS). Lithium is effective in the treatment and prophylaxis of major depression and shows significant immunoregulatory functions. Objective: The aims of the present study were to examine the in vitro effects of lithium on the unstimulated and lipolysaccharide (LPS) + phytohemagglutinin (PHA)-induced production of proinflammatory cytokines, such as interleukin-6 (IL-6), IL-8, tumor necrosis factor-α (TNFα) and interferon-γ (IFNγ), and negative immunoregulatory cytokines or proteins, such as IL-10 and the IL-1 receptor antagonist (IL-1RA). Methods: The in vitro effects of lithium carbonate at low (10−4 M and 10−5 M) and therapeutic (10−3 M) concentrations on the above cytokines and the IL-1RA were examined in nine healthy volunteers on whole blood supernatant cultured for 72 h. Results: Lithium (10−3 M) in the presence of LPS+PHA significantly increased the stimulated production of IFNγ, IL-8, TNFα, IL-1RA and IL-10. Lithium (10−3 M) significantly increased the unstimulated production of IL-8 and IL-10. Conclusions: The results suggest that lithium has significant immunoregulatory effects by increasing the production of both proinflammatory cytokines (IFNγ, TNFα and IL-8) and negative immunoregulatory cytokines or proteins (IL-10 and the IL-1RA).

Platelet [alpha]2-adrenoceptor density in humans: relationships to stress-induced anxiety, psychasthenic constitution, gender and stress-induced changes in the inflammatory response system

BACKGROUND This study examined the effects of psychological stress on platelet alpha2-adrenergic receptor (alpha2-AR) binding sites in relation to stress-induced anxiety and changes in the inflammatory response system (IRS). METHODS The maximum number of binding sites (Bmax) and their affinity (Kd) for [3H]rauwolscine, a selective alpha2-AR antagonist, and the stimulated production of tumor necrosis factor-alpha (TNFalpha), the Th1-like cytokine, interferon-gamma (IFNgamma), and the Th2-like cytokines, interleukin-10 (IL-10) and IL-5, were measured in 35 university students a few weeks before (baseline) as well as on the day before a difficult, oral examination (stress condition). The State-Trait-Anxiety Inventory (STAI) was recorded during both conditions. The Minnesota Multiphase Personality Inventory (MMPI-2) was used to assess psychasthenia (Scale 7). RESULTS Academic examination stress induced a significant increase in alpha2-AR density in students whose STAI scores increased in the stress period, in female students and in students who scored higher on psychasthenia. There were significant and positive correlations between stress-induced anxiety and changes in alpha2-AR density. Stress-induced anxiety was accompanied by a pro-inflammatory and Th1-like response, i.e. increased IFNgamma and TNFalpha production. The stress-induced changes in platelet alpha2-AR density were significantly and positively related to the production of TNFalpha, IL-10 and IL-5 and negatively to that of IFNgamma. CONCLUSIONS Subchronic psychological stress in humans induces increased alpha2-AR density, which is related to stress-induced anxiety, an anxiety-prone constitution and female sex. Increased alpha2-AR density is accompanied by a Th2-like response and increased TNFalpha production. The results suggest that: (i) alpha2-AR density is sensitive to graded differences in stress-induced anxiety; and (ii) psychological stress is accompanied by intertwined responses in the catecholaminergic system, such as alpha2-ARs, and the IRS, such as Th1/Th2-like functions and the production of TNFalpha.

The influence of psychological stress on total serum protein and patterns obtained in serum protein electrophoresis.

BACKGROUND Significant alterations in total serum protein (TSP) patterns obtained in serum protein electrophoresis and serum proteins have been reported in patients with major depression and in subjects submitted to a combination of psychological and physical stress. The aim of the present study was to examine the effects of academic examination stress, on TSP and patterns obtained in serum protein electrophoresis. METHODS TSP and the concentrations and percentages of the major electrophoretically separated serum proteins were measured in 41 healthy biomedical students the day before a difficult academic examination (i.e. the stressful condition), as well as a few weeks before and after the stressful condition (i.e. two baseline conditions). RESULTS Academic examination stress increased TSP and the alpha 1, alpha 2, beta and gamma concentrations in stress-reactors, but not in stress non-reactors (as defined by changes in the Perceived Stress Scale). Academic examination stress reduced the percentage of albumin in the stress-reactors, but not in stress non-reactors. There were significant positive relationships between the stress-induced changes in TSP and serum alpha 2, beta and gamma concentrations and the stress-induced changes in the Perceived Stress Scale. CONCLUSIONS The results show that even mild psychological stress of short duration can lead to measurable changes in TSP and in patterns obtained in serum protein electrophoresis.

Lower Serum Zinc in Relation to Serum Albumin and Proinflammatory Cytokines in Detoxified Alcohol-Dependent Patients without Apparent Liver Disease

Recently, it was reported that there may be an activation of the inflammatory response system in detoxified alcohol-dependent patients without apparent liver disease (AWLD). The aims of the present study were to examine serum zinc (Zn) concentrations, total serum protein (TSP) and patterns obtained in the electrophoretically separated protein fractions in relation to serum interleukin-6 (IL-6) and IL-8 concentrations in detoxified AWLD patients. Zn, TSP, SP electrophoresis, and serum IL-6 and IL-8 concentrations were determined in detoxified AWLD patients and age-matched healthy volunteers. Serum Zn, TSP and the serum concentrations of albumin (Alb) and the β fraction were significantly lower in detoxified AWLD patients than in healthy volunteers. The percentage of the α2 fraction was significantly higher in detoxified AWLD patients. Lower serum Zn in detoxified AWLD patients was attributable to lowered serum Alb. Lower serum Alb was significantly and negatively correlated to increased serum IL-8. The percentage of the α1 and α2 fractions were significantly and positively related to serum IL-6 and IL-8. The results show that there is an in vivo activation of the inflammatory response system in detoxified AWLD patients and that lower serum Zn may be causally related to lower serum Alb.