Response and habituation of pro- and anti-inflammatory gene expression to repeated acute stress

Brain Behav Immun. 2015 May:46:237-48. doi: 10.1016/j.bbi.2015.02.006. Epub 2015 Feb 12.


Introduction: Acute stress induces increases in plasma inflammatory mediators, which do not habituate to repeated stress. Inflammation is a risk factor for age-related illnesses, highlighting the need to understand factors controlling inflammation. No studies have examined changes in pro- and anti-inflammatory gene expression in response to repeated acute stress in humans.

Methods: RNA was isolated from peripheral blood before, 30 and 120min after exposure of n=32 healthy human participants to the Trier Social Stress Test (TSST) on two days. Gene expression of interleukin (IL)-6, IL-1β, nuclear factor (NF)-κB and IκB was measured repeatedly on both days. We further assessed leukocyte numbers, plasma IL-6, and salivary cortisol.

Results: Stress induced IL-6 (F=44.7; p<0.001) and cortisol responses (F=18.6; p<0.001). Cortisol responses habituated (F=5.1, p=0.003), but IL-6 responses did not (n.s.). All genes increased in response to initial stress (IL-6: F=3.8; p=0.029; IL-1β: F=7.1; p=0.008; NF-κB: F=5.1; p=0.009; IκB: F=4.7; p=0.013) and showed habituation to repeated stress (IL-6: t=2.3; p=0.03; IL-1β: t=3.9; p=0.001; NF-κB: t=2.1; p=0.041; IκB: t=3.1; p=0.005). Day 1 responses of IL-1β and IκB were not explained by changes in leukocyte populations, but IL-6 and NF-κB, as well as most day 2 changes were not independent of leukocyte populations.

Conclusions: Stress response and habituation of pro- and anti-inflammatory gene expression as found here might indicate that even on an intracellular level, inflammatory responses to acute stress are adaptive in that they respond to initial, but habituate to repeated, similar stress. Future studies will need to test whether non-habituation is predictive of disease.

Keywords: Gene expression; Habituation; IL-6, IL-1β, NF-κB, IκB; Inflammation; Stress.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Female
  • Gene Expression Regulation*
  • Humans
  • Hydrocortisone / analysis
  • Hypothalamo-Hypophyseal System / metabolism
  • I-kappa B Proteins / genetics*
  • I-kappa B Proteins / metabolism
  • Inflammation / genetics
  • Inflammation / metabolism
  • Interleukin-1beta / genetics*
  • Interleukin-1beta / metabolism
  • Interleukin-6 / genetics*
  • Interleukin-6 / metabolism
  • Male
  • Middle Aged
  • NF-kappa B / genetics*
  • NF-kappa B / metabolism
  • Pituitary-Adrenal System / metabolism
  • Saliva / chemistry
  • Stress, Psychological / genetics*
  • Stress, Psychological / metabolism
  • Young Adult


  • I-kappa B Proteins
  • IL6 protein, human
  • Interleukin-1beta
  • Interleukin-6
  • NF-kappa B
  • Hydrocortisone