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Research Article

Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk

Sheldon Cohen, Denise Janicki-Deverts, William J. Doyle, Gregory E. Miller, Ellen Frank, Bruce S. Rabin, and Ronald B. Turner
  1. aDepartment of Psychology, Carnegie Mellon University, Pittsburgh, PA 15213;
  2. bDepartment of Otolaryngology/ENT, Children's Hospital of Pittsburgh, Pittsburgh, PA 15224;
  3. cDepartment of Psychology, University of British Columbia, Vancouver, BC, Canada V6T 1Z4;
  4. Departments of dPsychiatry and
  5. ePathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; and
  6. fDepartment of Pediatrics, University of Virginia Health Sciences Center, Charlottesville, VA 22908

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PNAS first published April 2, 2012; https://doi.org/10.1073/pnas.1118355109
Sheldon Cohen
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  • For correspondence: scohen@cmu.edu
Denise Janicki-Deverts
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William J. Doyle
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Gregory E. Miller
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Ellen Frank
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Bruce S. Rabin
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Ronald B. Turner
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  1. Edited* by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved February 27, 2012 (received for review November 7, 2011)

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Abstract

We propose a model wherein chronic stress results in glucocorticoid receptor resistance (GCR) that, in turn, results in failure to down-regulate inflammatory response. Here we test the model in two viral-challenge studies. In study 1, we assessed stressful life events, GCR, and control variables including baseline antibody to the challenge virus, age, body mass index (BMI), season, race, sex, education, and virus type in 276 healthy adult volunteers. The volunteers were subsequently quarantined, exposed to one of two rhinoviruses, and followed for 5 d with nasal washes for viral isolation and assessment of signs/symptoms of a common cold. In study 2, we assessed the same control variables and GCR in 79 subjects who were subsequently exposed to a rhinovirus and monitored at baseline and for 5 d after viral challenge for the production of local (in nasal secretions) proinflammatory cytokines (IL-1β, TNF-α, and IL-6). Study 1: After covarying the control variables, those with recent exposure to a long-term threatening stressful experience demonstrated GCR; and those with GCR were at higher risk of subsequently developing a cold. Study 2: With the same controls used in study 1, greater GCR predicted the production of more local proinflammatory cytokines among infected subjects. These data provide support for a model suggesting that prolonged stressors result in GCR, which, in turn, interferes with appropriate regulation of inflammation. Because inflammation plays an important role in the onset and progression of a wide range of diseases, this model may have broad implications for understanding the role of stress in health.

  • lymphocytes
  • receptor sensitivity
  • psychological stress
  • cortisol
  • hypothalamic–pituitary–adrenocortical axis

Footnotes

  • ↵1To whom correspondence should be addressed. E-mail: scohen{at}cmu.edu.
  • Author contributions: S.C., W.J.D., and G.E.M. designed research; S.C., W.J.D., E.F., B.S.R., and R.B.T. performed research; E.F. and R.B.T. contributed new reagents/analytic tools; S.C. and D.J.-D. analyzed data; and S.C., D.J.-D., W.J.D., G.E.M., E.F., B.S.R., and R.B.T. wrote the paper.

  • The authors declare no conflict of interest.

  • ↵*This Direct Submission article had a prearranged editor.

Freely available online through the PNAS open access option.

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Stress, GCR, inflammation, and disease risk
Sheldon Cohen, Denise Janicki-Deverts, William J. Doyle, Gregory E. Miller, Ellen Frank, Bruce S. Rabin, Ronald B. Turner
Proceedings of the National Academy of Sciences Apr 2012, 201118355; DOI: 10.1073/pnas.1118355109

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Stress, GCR, inflammation, and disease risk
Sheldon Cohen, Denise Janicki-Deverts, William J. Doyle, Gregory E. Miller, Ellen Frank, Bruce S. Rabin, Ronald B. Turner
Proceedings of the National Academy of Sciences Apr 2012, 201118355; DOI: 10.1073/pnas.1118355109
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