Abstract Chronic stress is associated with morbidity and mortality from numerous conditions, many of whose pathogenesis involves persistent inflammation. Here, we examine how chronic stress ...influences signaling pathways that regulate inflammation in monocytes. The sample consisted of 33 adults caring for a family member with glioblastoma and 47 controls whose lives were free of major stressors. The subjects were assessed four times over eight months. Relative to controls, caregivers’ monocytes showed increased expression of genes bearing response elements for nuclear-factor kappa B, a key pro-inflammatory transcription factor. Simultaneously, caregivers showed reduced expression of genes with response elements for the glucocorticoid receptor, a transcription factor that conveys cortisol’s anti-inflammatory signals to monocytes. Transcript origin analyses revealed that CD14+/CD16− cells, a population of immature monocytes, were the predominate source of inflammatory gene expression among caregivers. We considered hormonal, molecular, and functional explanations for caregivers’ decreased glucocorticoid-mediated transcription. Across twelve days, the groups displayed similar diurnal cortisol profiles, suggesting that differential adrenocortical activity was not involved. Moreover, the groups’ monocytes expressed similar amounts of glucocorticoid receptor protein, suggesting that differential receptor availability was not involved. In ex vivo studies, subjects’ monocytes were stimulated with lipopolysaccharide, and caregivers showed greater production of the inflammatory cytokine interleukin-6 relative to controls. However, no group differences in functional glucocorticoid sensitivity were apparent; hydrocortisone was equally effective at inhibiting cytokine production in caregivers and controls. These findings may help shed light on the mechanisms through which caregiving increases vulnerability to inflammation-related diseases.
Social environmental influences on human health are well established in the epidemiology literature, but their functional genomic mechanisms are unclear. The present study analyzed genome-wide ...transcriptional activity in people who chronically experienced high versus low levels of subjective social isolation (loneliness) to assess alterations in the activity of transcription control pathways that might contribute to increased adverse health outcomes in social isolates.
DNA microarray analysis identified 209 genes that were differentially expressed in circulating leukocytes from 14 high- versus low-lonely individuals, including up-regulation of genes involved in immune activation, transcription control, and cell proliferation, and down-regulation of genes supporting mature B lymphocyte function and type I interferon response. Promoter-based bioinformatic analyses showed under-expression of genes bearing anti-inflammatory glucocorticoid response elements (GREs; p = 0.032) and over-expression of genes bearing response elements for pro-inflammatory NF-kappaB/Rel transcription factors (p = 0.011). This reciprocal shift in pro- and anti-inflammatory signaling was not attributable to differences in circulating cortisol levels, or to other demographic, psychological, or medical characteristics. Additional transcription control pathways showing differential activity in bioinformatic analyses included the CREB/ATF, JAK/STAT, IRF1, C/EBP, Oct, and GATA pathways.
These data provide the first indication that human genome-wide transcriptional activity is altered in association with a social epidemiological risk factor. Impaired transcription of glucocorticoid response genes and increased activity of pro-inflammatory transcription control pathways provide a functional genomic explanation for elevated risk of inflammatory disease in individuals who experience chronically high levels of subjective social isolation.
The first decade of adolescent and young adult (AYA) oncology psychosocial care and research (2005–2015) was driven by a normative, developmental framework that assumed a generalizable life ...experience for AYAs that is distinct from both younger children and older adults. As we proceed through a second decade, new considerations emerge regarding diversity of life experiences as occurring within and influenced by a complex global context. The purpose of this paper is to review and provide commentary on the impact of global and contextual conditions on AYAs. We expound upon the effects of precarious labor conditions, changing timetables and priorities for developmental tasks, sexual and gender plurality, and expanding cultural diversity. We discuss the implications of social genomics and technology and social media for enhancing precision psychosocial medicine. To build a forward‐looking approach, this paper calls for tailored, multilevel treatments that consider variability of AYAs within the social and global contexts in which they live.
To understand the mechanisms underlying chronic interpersonal difficulties and their detrimental influence on mental and physical health.
A total of 103 healthy young women (mean age = 17 years) were ...administered a structured interview to assess the degree of chronic interpersonal stress in their lives. At the same time, blood was drawn to measure systemic inflammation, the expression of signaling molecules that regulate immune activation, and leukocyte production of the cytokine interleukin-6 after ex vivo stimulation with lipopolysaccharide. All of the immunologic assessments were repeated 6 months later.
To the extent subjects were high in chronic interpersonal stress at baseline, their leukocytes displayed greater increases in messenger ribonucleic acid (mRNA) for the proinflammatory transcription factor nuclear factor-kappaB (NF-kappaB) over the next 6 months. They also showed larger increases in mRNA for inhibitor of kappaB, a molecule that sequesters NF-kappaB in the cytoplasm and minimizes its proinflammatory activities. Chronic interpersonal stress at baseline was unrelated to changes in biomarkers of systemic inflammation but was associated with increasingly pronounced interleukin-6 responses to lipopolysaccharide. These associations were independent of demographics, lifestyle variables, and depressive symptoms.
These findings suggest that chronic interpersonal difficulties accentuate expression of pro- and anti-inflammatory signaling molecules. Although this process does not result in systemic inflammation under quiescent conditions, it does accentuate leukocytes' inflammatory response to microbial challenge. These dynamics may underlie the excess morbidity associated with social stress, particularly in inflammation-sensitive diseases like depression and atherosclerosis.
Summary Background Although yoga and meditation have been used for stress reduction with reported improvement in inflammation, little is known about the biological mechanisms mediating such effects. ...The present study examined if a yogic meditation might alter the activity of inflammatory and antiviral transcription control pathways that shape immune cell gene expression. Methods Forty-five family dementia caregivers were randomized to either Kirtan Kriya Meditation (KKM) or Relaxing Music (RM) listening for 12 min daily for 8 weeks and 39 caregivers completed the study. Genome-wide transcriptional profiles were collected from peripheral blood leukocytes sampled at baseline and 8-week follow-up. Promoter-based bioinformatics analyses tested the hypothesis that observed transcriptional alterations were structured by reduced activity of the pro-inflammatory nuclear factor (NF)-κB family of transcription factors and increased activity of Interferon Response Factors (IRFs; i.e., reversal of patterns previously linked to stress). Results In response to KKM treatment, 68 genes were found to be differentially expressed (19 up-regulated, 49 down-regulated) after adjusting for potentially confounded differences in sex, illness burden, and BMI. Up-regulated genes included immunoglobulin-related transcripts. Down-regulated transcripts included pro-inflammatory cytokines and activation-related immediate-early genes. Transcript origin analyses identified plasmacytoid dendritic cells and B lymphocytes as the primary cellular context of these transcriptional alterations (both p < .001). Promoter-based bioinformatic analysis implicated reduced NF-κB signaling and increased activity of IRF1 in structuring those effects (both p < .05). Conclusion A brief daily yogic meditation intervention may reverse the pattern of increased NF-κB-related transcription of pro-inflammatory cytokines and decreased IRF1-related transcription of innate antiviral response genes previously observed in healthy individuals confronting a significant life stressor.
Experimental activation of the innate immune system has contributed significantly to both our understanding of how psychological factors influence immune function as well as how immune activity ...influences the brain and behavior. The annual influenza vaccine can be used to interrogate the effects of mild immune stimulation on day-to-day changes in psychological processes in human subjects that range across the lifespan and in both clinical and non-clinical populations. Yet, the immune response to the influenza vaccine in the days immediately following its administration are not well characterized. The present study describes changes in inflammatory and antiviral gene expression within circulating immune cells, plasma cytokines, and C-reactive protein (CRP) following receipt of the flu vaccine, and further reports the association between several common behavioral health factors and the acute immune response. Participants were 65 adults (mean age 18.81 ± 1.03 years; 66.2% female) who provided a blood sample immediately before and then 24 h after receiving the vaccine. A subsample also provided additional blood samples at 48 and 72 h. Plasma was assayed for CRP, IL-6, IL-10, IL-8, TNF-α, and IFN-γ, and peripheral blood mononuclear cell RNA was sequenced for evidence of change in expression of an a priori set of type 1 interferon (IFN) and inflammatory response genes (INFLAM). Plasma cytokines, CRP, and IFN response genes increased 24 h after vaccination, all ps < .001. The increase in IFN gene expression correlated with the observed increase in plasma cytokines and CRP, p < .0001. The immune response to influenza vaccination at 24-hours was moderated by anxiety symptoms, BMI, being female, sleep, and history of influenza vaccination. These factors and their associations with common immune challenges may be useful in studies interrogating the origins of immune dysregulation. The annual influenza vaccine is an accessible and reliable exogenous activator of both circulating and transcriptional markers of innate immune reactivity, with sensitivity to behavioral health factors relevant for psychoneuroimmunology research.
•Plasma cytokines and type 1 interferon response genes markedly increased 24 h after influenza vaccination.•Change in type 1 interferon gene expression correlated with increase in plasma cytokines.•Anxiety symptoms, female gender, and BMI increased innate inflammatory response to influenza vaccination.
Dispositional optimism, a personality trait predisposing individuals to positive expectations, has been suggested to promote better health. However, little is known about the biological mechanism of ...the salubrious health effects of optimism. We hypothesized that by diminishing a sense of threat to the self, optimism will be associated with a healthier profile of gene expression in immune cells. Specifically, the "conserved transcriptional response to adversity" (CTRA) is activated by fight-or-flight stress responses and results in increased transcription of genes involved in inflammation and decreased transcription of genes involved in antiviral defense. In a sample of 114 male Japanese workers, we found that optimism was inversely linked to CTRA after controlling for demographic variables, health-risk factors, and indices of well-being. These results are consistent with the hypothesis that reduced activity of threat-related gene expression programs may contribute to the health effects associated with optimism.
•A mindfulness meditation practice was associated with increased eudaimonic well-being in a sample of breast cancer survivors.•Increases in eudaimonic well-being correlated with decreases in the ...Conserved Transcriptional Response to Adversity (CTRA).•Eudaimonia-related CTRA reductions were driven primarily by increased expression of anti-viral and antibody-related genes.•The intervention was associated with reduced pro-inflammatory gene expression.•Changes in CTRA gene expression were not related to changes in distress or hedonic well-being.
The conserved transcriptional response to adversity (CTRA), characterized by increased expression of proinflammatory genes and decreased expression of antiviral and antibody-related genes, is upregulated in the context of chronic adversity and distress and has been linked to cancer progression. Several studies suggest that the CTRA may also be down-regulated in association with some positive psychological states, particularly eudaimonic well-being. However, it is not clear if the link between inter-individual differences in the CTRA and eudaimonic well-being can be extended to intra-individual change. Using a standardized mindfulness-based intervention, the current study tested whether mindfulness-related increases in eudaimonic well-being related to intra-individual reduction in the CTRA in a sample of younger breast cancer survivors.
Participants were 22 women who had been diagnosed and treated for early-stage breast cancer at or before age 50 (Mage = 46.6 years) and had no evidence of active disease. Women completed self-report questionnaires and provided peripheral blood samples before and after a 6-week mindfulness meditation intervention. Regression analyses were used to quantify associations between the magnitude of change in eudaimonic well-being and the magnitude of change in the global CTRA score.
Women reported significant increases in eudaimonic well–being and showed decreased expression of the pro-inflammatory subcomponent of the CTRA from pre- to post-intervention. The magnitude of increase in eudaimonic well-being was associated with the magnitude of decrease in the composite CTRA score, and this relationship was driven primarily by increased expression of the antiviral/antibody-related CTRA subcomponent. While the intervention was also associated with reduced depressive symptoms, there was no association between change in depressive symptoms and change in the overall CTRA composite score or either of its subcomponents.
Results are consistent with the hypothesis that eudaimonic well-being may be an important mechanism in interventions aimed at enhancing health in vulnerable groups, and contribute to our understanding of how psychological well-being may influence physical health in cancer patients.
•Animal models suggest parasympathetic nervous system (PNS) activity can inhibit inflammation.•In humans, PNS activity inversely associated with activity of pro-inflammatory NF-κB transcription ...control pathway.•PNS activity directly associated with up-regulation of Interferon Response Factors involved in innate antiviral responses.•Findings suggest enhancing PNS activity may favorably affect chronic diseases and host resistance to viral infections.
The vagus nerve mediates parasympathetic nervous system control of peripheral physiological processes including cardiovascular activity and immune response. In mice, tonic vagal activation down-regulates inflammation via nicotinic acetylcholine receptor-mediated inhibition of the pro-inflammatory transcription factor NF-κB in monocyte/macrophages. Because Type I interferon and pro-inflammatory genes are regulated reciprocally at the level of transcription factor activation and cell differentiation, we hypothesized that vagal activity would up-regulate Type I interferon response genes concurrently with inflammatory downregulation in human immune cells. We mapped empirical individual differences in the circulating leukocyte transcriptome and vagal activity indexed by high frequency (0.15–0.40 Hz) heart rate variability (HF-HRV) in 380 participants in the Midlife in the US study. Here we show that promoter-based bioinformatics analyses linked greater HF-HRV to reduced NF-κB activity and increased activity of IRF transcription factors involved in Type I interferon response (independent of β-antagonists, BMI, smoking, heavy alcohol consumption, and demographic factors). Transcript origin analyses implicated myeloid lineage immune cells as targets, representing per-cell alterations in gene transcription as HF-HRV was not associated with differential prevalence of leukocyte subsets. These findings support the concept of parasympathetic inhibition of pro-inflammatory gene expression in humans and up-regulation of Type I interferons that could augment host defense against viral infections.
This article is part of a Special Issue “Neuroendocrine-Immune Axis in Health and Disease.”
The regulation and function of the hypothalamic–pituitary–adrenocortical (HPA) axis and glucocorticoids ...have been well conserved across vertebrate species. Glucocorticoids influence a wide range of physiological functions that include glucose regulation, metabolism, inflammatory control, as well as cardiovascular, reproductive, and neuronal effects. Some of these are relatively quick-acting non-genomic effects, but most are slower-acting genomic effects. Thus, any stimulus that affects HPA function has the potential to exert wide-ranging short-term and long-term effects on much of vertebrate physiology. Here, we review the effects of social isolation on the functioning of the HPA axis in social species, and on glucocorticoid physiology in social mammals in particular. Evidence indicates that objective and perceived social isolation alter HPA regulation, although the nature and direction of the HPA response differs among species and across age. The inconsistencies in the direction and nature of HPA effects have implications for drawing cross-species conclusions about the effects of social isolation, and are particularly problematic for understanding HPA-related physiological processes in humans. The animal and human data are incommensurate because, for example, animal studies of objective isolation have typically not been modeled on, or for comparability with, the subjective experience of isolation in humans. An animal model of human isolation must be taken more seriously if we want to advance our understanding of the mechanisms for the effects of objective and perceived isolation in humans.
► Social isolation represents a survival threat to social species. ► Objective and perceived social isolation alter HPA regulation in social mammals. ► HPA responses to isolation differ among species and with age and duration. ► Chronic isolation is associated with a pro-inflammatory gene expression profile. ► Glucocorticoid resistance may explain higher morbidity in isolated individuals.
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