When Sheldon Cohen at Carnegie Mellon University exposed healthy adults to a rhinovirus and then tracked who got sick, he found that those who had experienced high levels of chronic stress in the preceding months were significantly more likely to develop a cold and to suffer more severe symptoms. This was not a new observation when the study was published in 1991, but Cohen has spent three decades elaborating the mechanisms by which stress activates inflammation and impairs immune regulation, producing a body of evidence that now makes the stress-inflammation link one of the most robust in psychoneuroimmunology.
The NF-kappaB Pathway
The primary molecular mechanism connecting psychological stress to inflammation runs through the transcription factor NF-kappaB, which controls the expression of inflammatory genes including those for IL-6, IL-1beta, and TNF-alpha. Chronic stress, via sustained sympathetic nervous system activation and cortisol, paradoxically upregulates NF-kappaB activity even while cortisol is meant to suppress inflammation acutely. The mechanism is glucocorticoid resistance: chronically stressed immune cells downregulate their cortisol receptors, losing sensitivity to cortisol's anti-inflammatory effects while remaining fully responsive to pro-inflammatory signals.
The Gut Component
Chronic stress increases intestinal permeability, allowing bacterial endotoxins and other luminal antigens to pass through the gut wall into the bloodstream. This activates toll-like receptors on immune cells and triggers systemic inflammatory responses that are entirely separate from the direct neural and hormonal pathway. The gut-brain axis therefore represents a second independent route by which psychological stress generates systemic inflammation.
Sources
- Cohen, S., et al. (2012). Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk. Proceedings of the National Academy of Sciences, 109(16), 5995-5999.
- Slavich, G.M., & Irwin, M.R. (2014). From stress to inflammation and major depressive disorder: a social signal transduction theory of depression. Psychological Bulletin, 140(3), 774-815.
- Dinan, T.G., & Cryan, J.F. (2012). Regulation of the stress response by the gut microbiota: implications for psychoneuroendocrinology. Psychoneuroendocrinology, 37(9), 1369-1378.