Trait sensitivity to social disconnection enhances pro-inflammatory responses to a randomized controlled trial of endotoxin

Psychoneuroendocrinology. 2015 Dec;62:336-42. doi: 10.1016/j.psyneuen.2015.08.020. Epub 2015 Aug 28.


One proposed mechanism for the association between social isolation and poor health outcomes is inflammation. Lonely or socially disconnected individuals show greater inflammatory responses, including up-regulation of pro-inflammatory gene expression, and people who are sensitive to cues of social disconnection (e.g., high levels of anxious attachment) exhibit greater inflammation in response to psychological stress. However, no studies have examined how sensitivity to social disconnection may influence pro-inflammatory responses to an inflammatory challenge. In the present study, we investigated the impact of sensitivity to social disconnection (a composite score comprised of loneliness, anxious attachment, fear of negative evaluation, and rejection sensitivity) on pro-inflammatory cytokines and gene expression in response to endotoxin, an inflammatory challenge, vs. placebo in a sample of one hundred and fifteen (n=115) healthy participants. Results showed that those who are more sensitive to social disconnection show increased pro-inflammatory responses (i.e., increased levels of tumor necrosis factor-alpha and interleukin-6) to endotoxin, as well as up-regulation of multiple genes related to inflammation. Furthermore, bioinformatics analyses revealed that those in the endotoxin group who are more sensitive to social disconnection exhibited a conserved transcriptional response to adversity (CTRA) regulatory profile, involving up-regulation of beta-adrenergic and pro-inflammatory transcription control pathways and down-regulation of antiviral transcription factors in response to endotoxin. These results may ultimately have implications for understanding the links between social isolation, inflammation, and health.

Clinical trials registration: NCT01671150.

Keywords: Cytokines; Endotoxin; Inflammation; Loneliness; Rejection sensitivity; Social genomics.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Double-Blind Method
  • Endotoxins / pharmacology*
  • Female
  • Humans
  • Inflammation / blood*
  • Inflammation / psychology
  • Interleukin-6 / blood*
  • Loneliness / psychology
  • Male
  • Personality*
  • Social Isolation*
  • Tumor Necrosis Factor-alpha / blood*
  • Young Adult


  • Endotoxins
  • IL6 protein, human
  • Interleukin-6
  • Tumor Necrosis Factor-alpha

Associated data