title: Greater inflammatory activity and blunted glucocorticoid signaling in monocytes of chronically stressed caregivers.
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.
authors.affiliation: Department of Psychology and Institute for Policy Research, Northwestern University, United States. Electronic address: greg.miller@northwestern.edu.
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Miller
authors.affiliation: Department of Psychology and Institute for Policy Research, Northwestern University, United States.
authors.forename: Michael L M
authors.initials: ML
authors.lastname: Murphy
authors.affiliation: British Columbia Cancer Agency, Vancouver Centre, Canada.
authors.forename: Rosemary
authors.initials: R
authors.lastname: Cashman
authors.affiliation: British Columbia Cancer Agency, Vancouver Centre, Canada.
authors.forename: Roy
authors.initials: R
authors.lastname: Ma
authors.affiliation: Division of Hematology-Oncology, UCLA School of Medicine, United States; UCLA AIDS Institute, Molecular Biology Institute, Jonsson Comprehensive Cancer Center, UCLA School of Medicine, United States; Norman Cousins Center at UCLA, United States.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Ma
authors.affiliation: Division of Hematology-Oncology, UCLA School of Medicine, United States; UCLA AIDS Institute, Molecular Biology Institute, Jonsson Comprehensive Cancer Center, UCLA School of Medicine, United States; Norman Cousins Center at UCLA, United States.
authors.forename: Jesusa M G
authors.initials: JM
authors.lastname: Arevalo
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, British Columbia Children's Hospital, Canada; Human Early Learning Partnership, School of Population and Public Health, University of British Columbia, Canada.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kobor
authors.affiliation: Division of Hematology-Oncology, UCLA School of Medicine, United States; UCLA AIDS Institute, Molecular Biology Institute, Jonsson Comprehensive Cancer Center, UCLA School of Medicine, United States; Norman Cousins Center at UCLA, United States.
authors.forename: Steve W
authors.initials: SW
authors.lastname: Cole
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D001932:Brain Neoplasms; D002097:C-Reactive Protein / Q000032:analysis; D017028:Caregivers / Q000523:psychology; D002478:Cells, Cultured; D002908:Chronic Disease; D005260:Female; D020869:Gene Expression Profiling; D005909:Glioblastoma; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism* / Q000494:pharmacology; D007249:Inflammation / Q000235:genetics / Q000276:immunology*; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology* / Q000502:physiology; D011965:Receptors, Glucocorticoid / Q000502:physiology*; D012463:Saliva / Q000737:chemistry; D015398:Signal Transduction / Q000276:immunology*; D013315:Stress, Psychological / Q000097:blood / Q000235:genetics / Q000276:immunology*; D014158:Transcription, Genetic
chemical_list: D015415:Biomarkers; D008070:Lipopolysaccharides; D011965:Receptors, Glucocorticoid; D002097:C-Reactive Protein; D006854:Hydrocortisone
keywords: Cytokines; Depression; Genomics; Glucocorticoids; Inflammation; Stress