One possible explanation for inflammation-related disease in individuals with high cortisol levels involves functional desensitization of the GR pathway that mediates transcriptional response to glucocorticoids. Several molecular mechanisms have been shown to render cells insensitive to the anti-inflammatory effects of glucocorticoids in vitro, including decreased expression of the GR NR3C1 gene, post-translational modification of GR protein, increased expression of GR antagonists, and decreased activity of GR transcription cofactors [37]. In both human and animal models, prolonged stress has been linked to reduced cellular expression of NR3C1 and increased cellular resistance to glucocorticoid inhibition of pro-inflammatory cytokine responses [37-40]. It is conceivable, therefore, that pro-inflammatory signaling persists in socially isolated people with high cortisol levels because impaired GR-mediated signal transduction prevents the cellular genome from effectively 'hearing' the anti-inflammatory signal sent by circulating glucocorticoids.
