Durk Pearson & Sandy Shaw’s®
Life Extension NewsTM
Volume 15 No. 3 • June/July 2012

Chronic Stress Interferes With Regulation of
Inflammation via Glucocorticoid Receptor Resistance

A considerable amount of research is being published on the subject of stress and inflammation. This is very useful since the more we understand how stress works, the more we can manipulate the process so as to avoid its most costly effects. In a new paper,1 researchers report that, in 276 human volunteers exposed to stressful life events (as determined in interviews with subjects) and then exposed to a rhinovirus (cause of the common cold), “those with recent exposure to a long-term threatening stressful experience demonstrated GCR [glucorticoid receptor resistance]; and those with GCR were at higher risk of subsequently developing a cold.”1

Glucocorticoid Receptor Resistance in COPD

Glucocorticoid receptor resistance is a potentially important mechanism of dysfunctional inflammation regulation that, by allowing pro-inflammatory mediators such as inflammatory cytokines to run wild, reduces the appropriate regulation of inflammatory processes. “Evidence for GCR in response to chronic stress has been found in parents of children with cancer, spouses of brain-cancer patients, and in persons reporting high levels of loneliness.” Because glucocorticoids are important in controlling inflammation, GCR can increase the risk for inflammatory conditions such as asthma and autoimmune diseases, as well as for conditions with chronic inflammation such as cardiovascular disease and type 2 diabetes1 as well as increasing the difficulty of treating inflammatory diseases such as COPD (chronic obstructive pulmonary disease).2

In another paper,3 higher body mass index was associated with reduced glucocorticoid inhibition of inflammatory cytokine production following psychosocial stress in men. This resulted in reduced ability to suppress TNF-alpha (an inflammatory cytokine) production that occurred during stress, prolonging inflammation and suggested to the researchers that “[t]his might suggest a new mechanism linking BMI [body mass index] with elevated risk for adverse cardiovascular outcomes following stress.”3 Blunted glucorticoid suppression of NF-kappaB, a key pro-inflammatory transcription factor, in human monocytes was also reported to result from stress,4 with the authors suggesting that “[t]his persistent activation of inflammatory mechanisms may contribute to stress-related morbidity and mortality.”

Restoring Glucocorticoid Sensitivity with Curcumin

Another paper5 reports that curcumin is able to restore corticosteroid sensitivity in human monocytes by maintaining levels of HDAC2 (histone deacetylase 2) which is known to be deficient in COPD and asthma patients. Deficiency of HDAC2 correlates with the severity of disease. The amount of curcumin required in vitro to restore HDAC2 activity and corticosteroid efficacy in cigarette smoke extract exposed cells is exceptionally small, having an EC(50) of approximately 30 nM (NANOmoles) and 200 nM (NANOmoles) respectively.5 Theophylline, a natural methylxanthine chemically related to caffeine, is also able to restore HDAC2 activity.6


  1. Cohen et al. Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk. Proc Natl Acad Sci USA 109(16):5995-9 (2012).
  2. Marwick et al. A role for phosphoinositol 3-kinase delta in the impairment of glucocorticoid responsiveness in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol 125(5):1146-53 (2010).
  3. Wirtz et al. Higher body mass index (BMI) is associated with reduced glucocorticoid inhibition of inflammatory cytokine production following acute psychosocial stress in men. Psychoneuroendocrinology 33:1102-10 (2008).
  4. Miller et al. A functional genomic fingerprint of chronic stress in humans: blunted glucocorticoid and increased NF-kappaB signaling. Biol Psychiatry 64:266-72 (2008).
  5. Meja et al. Curcumin restores corticosteroid function in monocytes exposed to oxidants by maintaining HDAC2. Am J Respir Cell Mol Biol 39(3):312-23 (2008). PMID: 18421014 [PubMed - indexed for ­MEDLINE]
  6. Marwick et al. Oxidative stress and steroid resistance in asthma and COPD: pharmacological manipulation of HDAC-2 as a therapeutic strategy. Expert Opin Ther Targets 11(6):745-55 (2007). PMID: 17504013 [PubMed - indexed for MEDLINE]

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