Experimental manipulation of social contact in animals can activate neuroendocrine signaling pathways [11-14], which have the potential to regulate gene expression in both pathogens (viruses, bacteria, tumors) and host immune responses [4,14-26]. No experimental studies have analyzed the transcriptional impact of chronic social isolation in humans, but data from observational studies suggest that subjective social isolation (loneliness) is associated with increased circulating levels of the stress hormone cortisol [27-30]. This adrenal glucocorticoid can regulate a wide variety of physiological processes via nuclear hormone receptor-mediated control of gene transcription [31]. Cortisol activation of the glucocorticoid receptor (GR) exerts broad anti-inflammatory effects by inhibiting nuclear factor (NF)-κB/Rel transcription factors and other pro-inflammatory signaling pathways (for example, the Janus kinase-signal transducer and activator of transcription (JAK/STAT) and interferon response factor (IRF) signaling) [32,33]. However, increased cortisol levels in chronically lonely individuals is paradoxical in light of the fact that most isolation-linked diseases are driven by increased inflammation (for example, lentiviral replication, atherosclerosis, and solid tissue malignancies) [34-36]. Given the broad anti-inflammatory effects of glucocorticoids, chronically lonely people with elevated cortisol levels should be relatively protected from inflammation-mediated disease rather than having the increased risk empirically observed.
