Cognitive-behavioral stress management reverses anxiety-related leukocyte transcriptional dynamics

Abstract

Background: Chronic threat and anxiety are associated with pro-inflammatory transcriptional profiles in circulating leukocytes, but the causal direction of that relationship has not been established. This study tested whether a cognitive-behavioral stress management (CBSM) intervention targeting negative affect and cognition might counteract anxiety-related transcriptional alterations in people confronting a major medical threat.

Methods: One hundred ninety-nine women undergoing primary treatment of stage 0-III breast cancer were randomized to a 10-week CBSM protocol or an active control condition. Seventy-nine provided peripheral blood leukocyte samples for genome-wide transcriptional profiling and bioinformatic analyses at baseline, 6-month, and 12-month follow-ups.

Results: Baseline negative affect was associated with >50% differential expression of 201 leukocyte transcripts, including upregulated expression of pro-inflammatory and metastasis-related genes. CBSM altered leukocyte expression of 91 genes by >50% at follow-up (group × time interaction), including downregulation of pro-inflammatory and metastasis-related genes and upregulation of type I interferon response genes. Promoter-based bioinformatic analyses implicated decreased activity of NF-κB/Rel and GATA family transcription factors and increased activity of interferon response factors and the glucocorticoid receptor as potential mediators of CBSM-induced transcriptional alterations.

Conclusions: In early-stage breast cancer patients, a 10-week CBSM intervention can reverse anxiety-related upregulation of pro-inflammatory gene expression in circulating leukocytes. These findings clarify the molecular signaling pathways by which behavioral interventions can influence physical health and alter peripheral inflammatory processes that may reciprocally affect brain affective and cognitive processes.

Trial registration: ClinicalTrials.gov NCT01422551.

Figure 1

Fold-difference in prevalence of Transcription Factor-Binding Motifs (TFBMs) targeted by the GR and IRF-, NF-κB/Rel-, and GATA-family transcription factors within the promoters of 29 genes found to be up-regulated in PBMC from CBSM-treated breast cancer patients relative to 62 genes up-regulated in active contact controls. V$ TFBM matrix names indicate vertebrate TRANSFAC position-specific weight matrices used in each analysis.

Figure 2

Bioinformatically inferred cellular origin of transcripts up- and down-regulated in PBMC from CBSM-treated breast cancer patients. Data represent the mean (± standard error) transcript origin diagnosticity score for the indicated cell type (8), with positive values indicating that differentially expressed genes originate disproportionately from the analyzed cell type and negative values uninformative (i.e., transcripts originate from other cell types, or from indicated cell type as well as other cell types).