In a very promising preliminary study, Miller and colleagues found that the pattern of gene expression differed between caregivers of family members with cancer relative to a matched group of individuals who did not have this type of life stress. They found that among the caregivers, even though they had normal cortisol levels in their blood, the pattern of gene expression in the monocytes, a type of white blood cell involved in the body's immune response, was altered so that they were relatively less responsive to the anti-inflammatory actions of cortisol, but relatively more responsive to pro-inflammatory actions of a transcription factor called nuclear factor-kappa B, or NF- B. Gregory Miller, Ph.D., corresponding author, explains more simply that, although "caregivers have similar cortisol levels as controls, their cells seem to be 'hearing' less of this signal. In other words, something goes awry in caregivers' white blood cells so they are not able to 'receive' the signal from cortisol that tells them to shut down inflammation."

Thus, the current findings might help to explain why the caregivers would seem to be in a chronic pro-inflammatory state, a condition of immunologic activation. This activated state could contribute to the risk for a number of medical illnesses, such as depression, heart disease, and diabetes. Dr. Miller remarks that part of the importance of these findings is "because people have traditionally thought that higher cortisol is the reason that stress contributes to disease, but this work shows that, at least in caregivers, it's actually the opposite - there's too little cortisol signal being heard by the cells, rather than too much."

However, many important related questions still remain unanswered, as noted by John H. Krystal, M.D., Editor of Biological Psychiatry and affiliated with both Yale University School of Medicine and the VA Connecticut Healthcare System. He comments that in addition to not knowing how stress produces these altered patterns of gene expression in the immune system, "we don't know how to account for the resilience of some stressed people exposed to severe sustained stress or the vulnerability of some people to relatively mild stress." He adds that "the better that we understand the underlying molecular mechanisms that link stress to illness, the more likely we are to make progress in answering these important questions," and this article is certainly a vital step in that direction. adequately to our available treatments."

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