A key contribution of the present study involves the use of recently developed structure/function bioinformatics to identify candidate upstream transcription control pathways that drive in vivo functional genomic alterations associated with social risk factors. Decreased activity of the anti-inflammatory GR pathway and reciprocal increases in NF-κB/Rel and JAK/STAT signaling represent plausible mediators of the increased immune activation profile observed in this study at the level of the leukocyte transcriptome. Reduced expression of GR-responsive genes is particularly remarkable in light of the fact that high-lonely individuals showed circulating cortisol levels that were broadly comparable to those of socially integrated individuals, and slightly higher during the late-day nadir in hypothalamic-pituitary-adrenal (HPA) axis output (consistent with previous findings) [27-30]. Thus, reduced expression of GR target genes in leukocytes from high-lonely individuals does not appear to stem from a failure of the HPA axis 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
