Abstract
Activation of the innate immune system is thought to contribute to depression. Multiple social and behavioral factors are also known to instigate depression. Whether these socio-behavioral factors interact with inflammatory stimuli to alter proinflammatory responses and depressed mood is not known. In 115 healthy adults, social, emotional, and behavioral factors were assessed at baseline. A single infusion of endotoxin (Escherichia coli; 0.8 ng/kg of body weight) or placebo (0.9% saline) was administered with hourly assessment of depressed mood and proinflammatory cytokines (interleukin-6 (IL-6); tumor necrosis factor-α (TNF)). Inflammatory gene expression was examined at 30 min after infusion, prior to increase of inflammatory cytokines. As compared to placebo, endotoxin-induced increases of depressed mood were moderated by baseline levels of perceived stress, trait sensitivity to social disconnection, and severity of symptoms of anxiety and depression (all Ps < 0.05) but not early life stress, social status, social support, neuroticism, or sleep disturbance. Anxiety symptoms remained significant in multivariable analyses (P < 0.01). None of these socio-behavioral factors were related to increases in proinflammatory cytokines. Transcriptome profiling analyses indicated that perceived stress, sensitivity to social disconnection, and depressive symptoms were associated with increased activation of pro-inflammatory transcription control pathways (i.e., activator protein-1, nuclear factor-κB) in response to endotoxin (all Ps < 0.05). These results indicate that an array of socio-behavioral factors, which are associated with depression risk, modify vulnerability to inflammation-induced depressed mood. Together, these observations may be used to help target therapeutic interventions to mitigate occurrence of the inflammatory biotype of depression.
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Acknowledgements
We thank Anthony Suffredini, MD, at the National Institutes of Health, Warren Grant Magnuson Clinical Center, for providing the standard reference endotoxin, the staff of the UCLA Clinical and Translational Research Center for providing technical assistance, the staff of the UCLA Cousins Center Inflammatory Biology Laboratory for laboratory and assay support, and the staff of the UCLA Statistical Consulting Group for providing statistical advice.
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This research was funded by an R01 from the National Institute of Mental Health to NIE (5R01MH091352). The authors also acknowledge the additional support provided by R01AG051944, R01AG026364, R01CA160245, and R01CA207130 to MRI; P30AG017265 and R01AG043404 to SWC; National Center for Advancing Translational Sciences UCLA CTSI Grant UL1TR001881; and the Cousins Center for Psychoneuroimmunology. Additionally, HJC was supported by K23AG049085, NIH/NCATS UCLA CTSI Grant KL2TR000122, and NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation. MRI, SC, HJC, and NIE have received funding from NIH. The other authors declare no competing interests.
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Irwin, M.R., Cole, S., Olmstead, R. et al. Moderators for depressed mood and systemic and transcriptional inflammatory responses: a randomized controlled trial of endotoxin. Neuropsychopharmacol 44, 635–641 (2019). https://doi.org/10.1038/s41386-018-0259-6
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DOI: https://doi.org/10.1038/s41386-018-0259-6
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