Jutta M. Wolf

A mechanism converting psychosocial stress into mononuclear cell activation

Little is known about the mechanisms converting psychosocial stress into cellular dysfunction. Various genes, up-regulated in atherosclerosis but also by psychosocial stress, are controlled by the transcription factor nuclear factor κB (NF-κB). Therefore, NF-κB is a good candidate to convert psychosocial stress into cellular activation. Volunteers were subjected to a brief laboratory stress test and NF-κB activity was determined in peripheral blood mononuclear cells (PBMC), as a window into the body and because PBMC play a role in diseases such as atherosclerosis. In 17 of 19 volunteers, NF-κB was rapidly induced during stress exposure, in parallel with elevated levels of catecholamines and cortisol, and returned to basal levels within 60 min. To model this response, mice transgenic for a strictly NF-κB-controlled β-globin transgene were stressed by immobilization. Immobilization resulted in increased β-globin expression, which could be reduced in the presence of the α1-adrenergic inhibitor prazosin. To define the role of adrenergic stimulation in the up-regulation of NF-κB, THP-1 cells were induced with physiological amounts of catecholamines for 10 min. Only noradrenaline resulted in a dose- and time-dependent induction of NF-κB and NF-κB-dependent gene expression, which depended on pertussis-toxin-sensitive G protein-mediated phosphophatidylinositol 3-kinase, Ras/Raf, and mitogen-activated protein kinase activation. Induction was reduced by α1- and β-adrenergic inhibitors. Thus, noradrenaline-dependent adrenergic stimulation results in activation of NF-κB in vitro and in vivo. Activation of NF-κB represents a downstream effector for the neuroendocrine response to stressful psychosocial events and links changes in the activity of the neuroendocrine axis to the cellular response.

Psychosocial stress-induced activation of salivary alpha-amylase: an indicator of sympathetic activity?

Abstract: Assessment of sympathoadrenal medullary system (SAM) activity is only possible to date via measurement of catecholamines in blood plasma or via electrophysiological methods. Both ways of measurement are restricted to endocrinological or psychophysiological laboratories, as both require either immediate freezing of blood samples or complex recording devices. Efforts have therefore been undertaken to find a method comparable to salivary cortisol measurements, in which noninvasive samples can be taken at any place and stored at room temperature for sufficient time before later analysis in the laboratory. Salivary alpha‐amylase (sAA) is a candidate that may prove useful in this context. We show here that sAA activity is increased by acute psychosocial stress (Trier Social Stress Test) and that increases in sAA correlate with increases in norepinephrine. We further report that sAA exhibits a stable circadian pattern that mirrors that of salivary cortisol. In conclusion, the current data show that salivary alpha‐amylase may serve as an easy‐to‐use index for SAM activity. However, some questions remain to be answered; for example, what impact does salivary flow rate exert on stress‐induced sAA activity?

Hypocortisolism and increased glucocorticoid sensitivity of pro-inflammatory cytokine production in Bosnian war refugees with posttraumatic stress disorder

BACKGROUND Posttraumatic stress disorder (PTSD) is associated with dysregulation of the hypothalamus pituitary adrenal (HPA) axis. Alterations include various responses to HPA axis stimulation, different basal hormone levels, and changes in glucocorticoid receptor (GR) numbers on lymphocytes. The functional significance of these latter changes remains elusive. METHODS Twelve Bosnian war refugees with PTSD and 13 control subjects were studied. On 2 consecutive days, they collected saliva samples after awakening and at 11, 15, and 20 hours. Glucocorticoid (GC) sensitivity was measured by dexamethasone (DEX) inhibition of lipopolysaccharide (LPS)-induced interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) production in whole blood. RESULTS The PTSD patients showed no cortisol response after awakening and had lower daytime cortisol levels (F = 14.57, p <.001). Less DEX was required for cytokine suppression in PTSD patients (IL-6: t = -2.82, p =.01; TNF-alpha: t = 5.03, p <.001), reflecting higher GC sensitivity of pro-inflammatory cytokine production. The LPS-stimulated production of IL-6, but not TNF-alpha, was markedly increased in patients (IL-6: F = 10.01, p <.004; TNF-alpha: F =.89, p =.34). CONCLUSIONS In refugees with PTSD, hypocortisolism is associated with increased GC sensitivity of immunologic tissues. Whether this pattern reflects an adaptive mechanism and whether this is sufficient to protect from detrimental effects of low cortisol remains to be investigated.

Stress on the dance floor: the cortisol stress response to social-evaluative threat in competitive ballroom dancers.

The social self-preservation theory states that humans have a fundamental motivation to preserve the social self and that threats to the social self perturb biological markers such as cortisol. Five studies were designed to examine the cortisol response to competitive ballroom dancing as a paradigm for real-life social-evaluative threat. Competitive dancing produced substantial increases in cortisol compared to a control day. These increases were not due to the physical strain of dancing and were greater than those found during social-evaluative laboratory stressors. Responses did not habituate across competitions and were mostly elevated under highly focused conditions of threat (couple vs. group competition). These findings support the notion of a social self-preservation system that is physiologically responsive to threats to the social self.

Chronic stress, salivary cortisol, and α-amylase in children with asthma and healthy children

The present study examined whether chronic stress is related to daily life levels of salivary alpha-amylase (sAA), a marker for sympathetic activity, and cortisol in healthy children versus children with asthma. Childrens sAA and cortisol levels were measured repeatedly over 2 days. Chronic stress measures included interviews with children about chronic home life stress and interviews with parents about one marker of socioeconomic status, parental education. Among children with asthma, higher chronic stress was associated with lower daily sAA output, while among healthy children, higher chronic stress was associated with flatter cortisol slopes. In conclusion, chronically stressed children with asthma showed lower salivary alpha-amylase output, indicating lower sympathetic activity, and implying a possible mechanism for increased susceptibility to symptom exacerbations. In contrast, higher cortisol levels in healthy children with chronic stress may indicate, for example, an increased risk for infectious diseases. This dichotomy emphasizes the different biological effects of chronic stress depending on illness status.

Acute stress responses in salivary alpha-amylase predict increases of plasma norepinephrine

Current biobehavioral research increasingly employs salivary alpha-amylase (sAA) as a surrogate marker for sympathetic nervous system (SNS) activity. While different lines of evidence point to the validity of this assumption, the literature is inconsistent with regard to associations of sAA with well-established SNS indicators, such as plasma norepinephrine (NE) or epinephrine (E). Small samples as well as application of different stress paradigms might be responsible. This study therefore set out to examine the relation between stress-induced sAA activity with NE and E by exposing a larger and less constrained sample to an effective stress protocol. Sixty-six healthy participants (mean age 24.30±4.24 yrs), including n=40 women, n=26 men, n=18 oral contraceptive (OC) users, and n=15 habitual smokers, were recruited and subjected to the Trier Social Stress Test (TSST). Saliva and blood samples were taken at four time points throughout the experiment for later analysis of sAA activity and NE/E concentration, respectively. As expected, sAA, NE, and E showed significant increases in response to the acute stress induction (all p<0.001). Regression analyses (controlling for age, BMI, sex, smoking and OC) revealed that stress responses in sAA significantly predicted stress responses in NE (r=0.326; p=0.025). Interestingly, stress responses in E predicted NE to a lesser extend (β=0.265; p=0.064). E responses showed no association with sAA (β=0.265; p=0.064). Higher sAA levels were found in habitual smokers (F=4.27; p=0.043) and in individuals with lower BMI (F=2.81; p=0.099). In conclusion, current data clearly show an association between stress responses of sAA and plasma NE. This relationship is stronger than the association of norepinephrine and epinephrine responses, thus placing the predictive power of sAA well within the expected range for different SNS markers.

Glucocorticoid sensitivity of cognitive and inflammatory processes in depression and posttraumatic stress disorder.

Both hyper- and hypo-activity of the hypothalamus-pituitary-adrenal (HPA) axis activity are a consistently reported hallmark feature of stress-related disorders, such as major depression and posttraumatic stress disorder (PTSD), respectively. In this manuscript, however, we are summarizing evidence pointing to altered glucocorticoid (GC) sensitivity in relevant target tissues for HPA axis hormones. Specifically, we provide a summary of GC effects on cognitive functions, as an emerging marker for central nervous system GC sensitivity, and of GC effects on peripheral inflammatory responses. With regard to depression and PTSD, evidence thereby points to decreased GC sensitivity of the cognitive and inflammatory systems in depression, and increased GC sensitivity of both systems in PTSD. Taken together, these data support the hypothesis that both psychiatric disorders are characterized by inefficient GC signaling, although through dysregulations at different levels. Potential underlying pathways and implications are discussed.

Glucocorticoid Sensitivity in Humans-Interindividual Differences and Acute Stress Effects

The hypothalamus pituitary adrenal (HPA)- axis is one of the major output systems of the neuroendocrine stress response. Its major end products, glucocorticoids (GCs), have a plethora of effects throughout the organism, most of which are believed to be protective against disturbances of homeostasis. However, negative effects have also been described under specific conditions of hyper- or hypo(re)activity of the HPA axis. Both beneficial and adverse effects of GCs ultimately depend on the target tissue sensitivity to these steroids. Recent findings suggest that GC sensitivity (a) may vary between different target tissues in the same organism, (b) shows large individual differences and (c) can be acutely changed in times of acute stress. In the present review, data are summarized which show differences in GC sensitivities in patients suffering from diverse somatic and psychiatric diseases, as well as chronically stressed individuals. Furthermore, studies are presented that show a rapid modulation of GC sensitivity in response to exercise or psychosocial stress in healthy adults. The response pattern of acute GC sensitivity modulation seems to be influenced by age and sex hormone status of the individual. While the GC signalling cascade may be subject to modulation at several levels, the pathway for acute modulation of GC sensitivity remains to be elucidated.

Age and sex steroid-related changes in glucocorticoid sensitivity of pro-inflammatory cytokine production after psychosocial stress

Aging is associated with an increased susceptibility to infections and chronic inflammatory diseases. This might be caused by dysregulations of the endocrine system with increased activity of the hypothalamus-pituitary-adrenal (HPA) axis and decreased levels of sex steroids. Therefore, we investigated the stress-response of the HPA axis and glucocorticoid (GC) sensitivity of pro-inflammatory cytokine production in elderly men, compared to testosterone-treated elderly men and young controls. Stress-induced increases in cortisol did not differ significantly between experimental groups (F=2.10; p>0.10), but GC sensitivity increased significantly in young controls and testosterone-treated elderly men, while a decrease was found in untreated elderly men (F=5.28; p<0.01). We conclude that the increase in GC sensitivity after stress serves to protect the individual from detrimental increases of pro-inflammatory cytokines, a mechanism that is disturbed in elderly men and partly restored by testosterone treatment.

Parent psychological states predict changes in inflammatory markers in children with asthma and healthy children.

Previous research has shown that parent mental health is associated with asthma morbidity in children. However, the biological pathways explaining these relationships are not known. The present study tested whether parent psychological characteristics could predict longitudinal changes in inflammatory markers in children with asthma and a comparison group of healthy children. For this, 33 healthy children (17 m/16 f; 13.5 years) and 50 children with asthma (37 m/13 f; 13.3 years) were assessed at two time points on average 208 days apart. Parent depression (CES-D) and perceived stress (PSS) were assessed at baseline, child depression (CDI) and anxiety (RCMAS) at follow-up. Asthma-relevant inflammatory markers eosinophil cationic protein (ECP) and stimulated interleukin-4 (IL-4) production were measured at baseline and at follow-up. Hierarchical regression analyses controlling for asthma severity and medication use revealed that higher levels of parental perceived stress at baseline were associated with greater increases over time in childrens IL-4 production (beta=.29, p=.019) as well as ECP release (beta=.27, p=.004). Additionally, higher levels of parental depression at baseline were associated with increases in ECP over time (beta=.19, p=.046). There was no evidence that these associations were mediated by child depression or anxiety. These results demonstrate that parental stress and depression at baseline predict increases in childrens inflammatory profiles over a six month period. This pattern appeared in both children with asthma and healthy children, and was not due to effects on child psychological states. These changes in inflammatory makers may represent one biological mechanism underlying the association between parental distress and child asthma morbidity.