in orchestrating both patterns of differential gene expression. Results also suggested that the GR was failing to inhibit NF-κB’s pro-inflammatory activity as it should. Neither study found decreases in circulating cortisol levels that might explain the reduced GR activity. If the HPA axis were sending the proper anti-inflammatory cortisol signal, why would stressed people’s leukocytes not down-regulate NF-κB transcription of inflammatory genes? The answer appears to involve a reduction in the GR’s sensitivity to cortisol – rendering the leukocyte transcriptome deaf to the brain’s request to down-regulate pro-inflammatory genes (Cole et al., 2007; Miller et al., 2008). Both chronic loneliness and threat of social loss appear to disconnect this key physiologic feedback system, and may thereby increase the risk of inflammation-related disease (Seeman, 1996). Similar analyses have identified other alterations in transcription factor activity that may connect low SES to inflammatory gene expression in asthma (Chen et al., 2008), and connect low social support and depression to altered gene expression in ovarian cancer (Lutgendorf et al., 2008).
