Background Chronic stressors are known to increase vulnerability to medical illness, but the mechanisms underlying this phenomenon are poorly understood. Methods To identify transcriptional control ...pathways that are modified by chronic stress, we conducted genomewide expression microarrays on familial caregivers of brain-cancer patients (n = 11) and matched control subjects (n = 10). Analyses were conducted on peripheral blood monocytes, which are cells that have the ability to initiate and maintain many inflammatory responses. Salivary cortisol was collected over the course of 3 days as volunteers went about normal activities. Results Caregivers' patterns of cortisol secretion were similar to those of matched control subjects. However, their monocytes showed diminished expression of transcripts bearing response elements for glucocorticoids, and heightened expression of transcripts with response elements for NF-κB, a key pro-inflammatory transcription factor. Caregivers also showed relative elevations in the inflammatory markers C-reactive protein and interleukin-1 receptor antagonist. Conclusions These findings suggest that even in the absence of excess adrenocortical output, stress brings about functional resistance to glucocorticoids in monocytes, which enables activation of pro-inflammatory transcription control pathways. This persistent activation of inflammatory mechanisms may contribute to stress-related morbidity and mortality.
•Non-invasive removal of a primary tumor can induce dormancy in micro-metastases.•Major surgery can prevent such dormancy, causing a delayed metastatic outbreak.•Surgery can elevate secretion of ...pro-metastatic factors from primary tumors.•Adrenergic & prostanoid signaling mediate these deleterious effects of surgery.•Tumor IL-6, IL-8, and VEGF potentially mediate surgery-induced escape from dormancy.
We recently showed that a minimally-invasive removal of MDA-MB-231HM primary tumors (PTs) and elimination of their secreted factors (including IL-6, IL-8, VEGF, EGF, PDGF-aa, MIF, SerpinE1, and M−CSF), caused regression of spontaneous micro-metastases into a non-growing dormant state. To explore the underlying mechanisms and potential clinical ramifications of this phenomenon, we herein used the MDA-MB-231HM human breast cancer cell-line, in-vitro, and in vivo following orthotopic implantation in immune-deficient BALB/C nu/nu mice. Employing bioluminescence imaging, we found that adding laparotomy to minimally-invasive removal of the PT caused an outbreak of micro-metastases. However, perioperative β-adrenergic and COX-2 inhibition, using propranolol + etodolac, maintained metastatic dormancy following laparotomy. In-vitro, β-adrenergic agonists (epinephrine or metaproterenol) and prostaglandin-E2 markedly increased MDA-MB-231HM secretion of the pro-metastatic factors IL-6, IL-8, and VEGF, whereas cortisol reduced their secretion, effects that were maintained even 12 h after the washout of these agonists. In-vivo, laparotomy elevated IL-6 and IL-8 levels in both plasma and ex-vivo PT spontaneous secretion, whereas perioperative propranolol + etodolac administration blocked these effects. Similar trends were evident for EGF and MIF. Promoter-based bioinformatics analyses of excised PT transcriptomes implicated elevated NF-kB activity and reduced IRF1 activity in the gene regulatory effects of laparotomy, and these effects were inhibited by pre-surgical propranolol + etodolac. Taken together, our findings suggest a novel mechanism of post-operative metastatic outbreak, where surgery-induced adrenergic and prostanoid signaling increase the secretion of pro-metastatic factors, including IL-6, IL-8, and VEGF, from PT and possibly residual malignant tissue, and thereby prevent residual disease from entering dormancy.
Inflammation has been shown to predict depression, but sensitivity to inflammation varies across individuals. Experimental studies administering potent pro-inflammatory agents have begun to ...characterize this sensitivity. However, risk factors for inflammation-associated depression in naturalistic contexts have not been determined. The present study examined key psychological and behavioral risk factors (state anxiety, perceived stress, negative affect, disturbed sleep, and childhood adversity) as potential moderators of the relationship between inflammation and depressive symptoms in a prospective longitudinal study of breast cancer survivors. Women with early stage breast cancer were recruited after completing primary cancer treatment (n
= 161). Depressive symptoms, inflammatory markers (CRP, IL-6, and sTNF-RII), and key risk factors were assessed post treatment (T1), at 6 and 12-month follow-ups (T2 and T3), and during a final follow-up (TF) 3-6 years after T1; childhood adversity was measured only at T3. Inflammatory markers were combined into a single inflammatory index prior to analyses. Women who reported higher levels of state anxiety, perceived stress, negative affect, and/or sleep disturbance at T1 (post-treatment) exhibited higher depressive symptoms at times when inflammation was higher than typical (interaction βs ranged from .06 to .08; all ps < .014). Results demonstrate the relevance of these risk factors for understanding inflammation-associated depression in a clinical context and could inform targeted strategies for prevention and treatment among at-risk populations.
The use of environmental enrichment (EE) has grown in popularity over decades, particularly because EE is known to promote cognitive functions and well-being. Nonetheless, little is known about how ...EE may affect personality and gene expression. To address this question in a domestic animal, 10-month-old horses were maintained in a controlled environment or EE for 12 weeks. The control horses (n = 9) lived in individual stalls on wood shaving bedding. They were turned out to individual paddocks three times a week and were fed three times a day with pellets or hay. EE-treated horses (n = 10) were housed in large individual stalls on straw bedding 7 hours per day and spent the remainder of the time together at pasture. They were fed three times a day with flavored pellets, hay, or fruits and were exposed daily to various objects, odors, and music. The EE modified three dimensions of personality: fearfulness, reactivity to humans, and sensory sensitivity. Some of these changes persisted >3 months after treatment. These changes are suggestive of a more positive perception of the environment and a higher level of curiosity in EE-treated horses, explaining partly why these horses showed better learning performance in a Go/No-Go task. Reduced expression of stress indicators indicated that the EE also improved well-being. Finally, whole-blood transcriptomic analysis showed that in addition to an effect on the cortisol level, the EE induced the expression of genes involved in cell growth and proliferation, while the control treatment activated genes related to apoptosis. Changes in both behavior and gene expression may constitute a psychobiological signature of the effects of enrichment and result in improved well-being. This study illustrates how the environment interacts with genetic information in shaping the individual at both the behavioral and molecular levels.
•Prenatal life stress predicted third trimester pro-inflammatory gene expression.•Pro-inflammatory gene expression patterns were regulated by NF-kB and AP-1.•Preconception life stress was not ...associated with third trimester gene expression.
Stress exposure is associated with risk for adverse pregnancy outcomes, potentially in part through dysregulated immune and inflammatory activity. Evidence suggests that stress during pregnancy is associated with inflammation during pregnancy, consistent with risk for preterm birth. However, research has not tested whether complementary changes are reflected in immune cell gene expression, or upstream regulation of inflammation. The purpose of this study was to test associations between preconception and prenatal stress exposure and third trimester immune cell gene expression, focusing specifically on sets of genes previously linked to stress in non-pregnant samples: Pro-inflammatory genes, and antiviral and antibody genes.
A sample of 116 low-income, diverse women was recruited from 5 U.S. sites by the Community Child and Health Network at the birth of a child. This study is of the subgroup of women who became pregnant again over the two-year follow-up period, and provided information on stressful life events that occurred both preconception and during the third trimester of the subsequent pregnancy. Dried blood spots (DBS) were collected in the third trimester of pregnancy, and used for gene expression analysis.
Women with more prenatal stressful life events had higher expression of pro-inflammatory genes when compared to those with fewer life events, and the effect was driven by increased activation of pro-inflammatory transcription factors, NF-κB and AP-1. Preconception stressful life event exposure was not associated with gene expression profiles. When entered into models simultaneously, only prenatal stressful life events were associated with up-regulation of pro-inflammatory genes. No differences between high or low stress groups emerged for antiviral or antibody genes.
Prenatal stress exposure was associated with up-regulated pro-inflammatory gene expression during pregnancy, and increased activity of NF-κB and AP-1. In contrast, stress occurring preconception was not associated with gene expression. These results are consistent with the hypothesis that stress-induced activation of pro-inflammatory transcriptional pathways in pregnancy, but not earlier, may increase risk for inflammation-driven adverse pregnancy outcomes.
This review surveys empirical research pertinent to the hypothesis that activity of the hypothalamus-pituitary-adrenal (HPA) axis and/or the sympathetic nervous system (SNS) might mediate ...biobehavioral influences on HIV-1 pathogenesis and disease progression. Data are considered based on causal effects of neuroeffector molecules on HIV-1 replication, prospective relationships between neural/endocrine parameters and HIV-relevant biological or clinical markers, and correlational data consistent with in vivo neural/endocrine mediation in human or animal studies. Results show that HPA and SNS effector molecules can enhance HIV-1 replication in cellular models via effects on viral infectivity, viral gene expression, and the innate immune response to infection. Animal models and human clinical studies both provide evidence consistent with SNS regulation of viral replication, but data on HPA mediation are less clear. Regulation of leukocyte biology by neuroeffector molecules provides a plausible biological mechanism by which psychosocial factors might influence HIV-1 pathogenesis, even in the era of effective antiretroviral therapy. As such, neural and endocrine parameters might provide useful biomarkers for gauging the promise of behavioral interventions and suggest novel adjunctive strategies for controlling HIV-1 disease progression.
The experience of cancer elicits not only turmoil but also resilience in the family, which has been related to psychological adjustment and physical health of family caregivers. The biological ...pathways linking family cancer caregiving to health, however, remain poorly understood. This study examined the extent to which psychological risk and resilience factors related to a proinflammatory gene expression profile (conserved transcriptional response to adversity, or CTRA) among caregivers during the first-year postdiagnosis of a patient with colorectal cancer.
A total of 41 caregivers (mean age = 54 years, 74% female, 40% Hispanic) provided psychological data and peripheral blood samples around 4 and 12 months after diagnosis. Mixed regression models controlling for demographic and biometric factors were used to test the associations of caregiver CTRA gene expression with caregiving stress, loneliness, and lack of social support (risk factors), as well as benefit finding and meaning (resilience factors).
When individually tested, all but benefit finding were significantly related to CTRA (R2 ≥ 0.112, p < .045). When adjusted for other factors in either the risk or resilience group, loneliness, social support, and meaning effects remained significant (R2 ≥ 0.120, p < .041). When all study factors were simultaneously adjusted (R2 = 0.139), only loneliness remained significant (p = .034).
Findings suggest that caregiving-related transcriptional effects seem to be most pronounced when caregivers experience low social support and loneliness, as well as little meaning or purpose in their caregiving. These findings suggest that the development of new intervention strategies that prioritize reductions in caregiver loneliness may favorably impact biological mechanisms related to caregiver health.
To examine the association between the experience of daily interpersonal stress and levels of C-reactive protein (CRP), an inflammatory marker that is a key indicator of cardiovascular risk, during ...the teenage years.
A total of 69 adolescents (Mage= 17.78 years) completed daily diary checklists each night for 14 days in which they reported their experience of negative interpersonal interactions in the domains of family, peers, and school (e.g., conflict with family and friends, peer harassment, punishment by parents and teachers). Blood samples were obtained an average of 8.63 months later and assayed for circulating levels of CRP, using enzyme-linked immunosorbent assay. Measures of body mass index (BMI), socioeconomic status (SES), substance use, stressful life events, rejection sensitivity, and psychological distress were obtained.
A greater frequency of daily interpersonal stress was associated with higher levels of CRP, even after controlling for BMI, SES, substance use, life events, rejection sensitivity, psychological distress, and frequency of daily interpersonal stress 2 years earlier.
Experiencing a high frequency of interpersonal stressors that are typical of adolescent life is associated with higher levels of inflammation even among a normative, healthy sample of adolescents. Additional work should focus on other daily experiences during the adolescent period and their implications for elevated risk for later cardiovascular disease.
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