to maintain normal circulating cortisol levels, but rather from a reduction in GR-mediated transduction of that hormonal signal into the cellular transcriptome. This hypothesis is consistent with previous indications of receptor-mediated glucocorticoid insensitivity during behavioral stress [38,40], and with recently identified molecular mechanisms of GR transcriptional inhibition [37]. Loneliness was not associated with a reduction in GR (NR3C1) mRNA levels, suggesting that post-transcriptional modification of the GR is the most likely mechanism of transcriptional inhibition [37]. Further analyses will be required to identify the specific molecular locus of GR desensitization, but the broad alterations in inflammatory gene expression identified in the present study suggest that the GR's functional modification has physiological significance at the level of in vivo gene regulation. Thus, human genomic function is indeed sensitive to social environmental conditions, but transcriptional alterations may not always track alterations in neuroendocrine activity due to intervening variations in the activity of signal transduction pathways (for example, GR insensitivity).
