Inflammation Versus Glucocorticoids as Purveyors of Pathology During Stress: Have We Reached the Tipping Point?

Department of Psychiatry and Behavioral Sciences, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Biological psychiatry (Impact Factor: 10.26). 09/2008; 64(4):263-5. DOI: 10.1016/j.biopsych.2008.05.018
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Available from: Andrew H Miller, Dec 22, 2013
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    • "Depending on the stressor (i.e. the nature, the intensity and the duration of the threat), neuroendocrine modulation of immunity may be beneficial or detrimental (Anisman, 2009; Dantzer et al., 2008). For instance, immune dysfunction and behavioral disturbances have been associated with chronic or repeated exposure to stress, and elevated levels of circulating proinflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-a) have been associated with mood disturbances such as anxiety and depression (Miller, 2008; Pace et al., 2006). Furthermore, stressful experiences can induce activation of many aspects of both peripheral immunity and central neuroimmune processes, both of which contribute to various forms of host defense, recovery from stress and ultimately disease susceptibility. "
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    ABSTRACT: The last decade has witnessed profound growth in studies examining the role of fundamental neuroimmune processes as key mechanisms that might form a natural bridge between normal physiology and pathological outcomes. Rooted in core concepts from psychoneuroimmunology, this review utilizes a succinct, exemplar-driven approach of several model systems that contribute significantly to our knowledge of the mechanisms by which neuroimmune processes interact with stress physiology. Specifically, we review recent evidence showing that (i) stress challenges produce time-dependent and stressor-specific patterns of cytokine/chemokine expression in the CNS; (ii) inflammation-related genes exhibit unique expression profiles in males and females depending upon individual, cooperative or antagonistic interactions between steroid hormone receptors (estrogen and glucocorticoid receptors); (iii) adverse social experiences incurred through repeated social defeat engage a dynamic process of immune cell migration from the bone marrow to brain and prime neuroimmune function and (iv) early developmental exposure to an inflammatory stimulus (carageenin injection into the hindpaw) has a lasting influence on stress reactivity across the lifespan. As such, the present review provides a theoretical framework for understanding the role that neuroimmune mechanisms might play in stress plasticity and pathological outcomes, while at the same time pointing toward features of the individual (sex, developmental experience, stress history) that might ultimately be used for the development of personalized strategies for therapeutic intervention in stress-related pathologies.
    Stress (Amsterdam, Netherlands) 07/2015; 18(4):1-14. DOI:10.3109/10253890.2015.1053451 · 2.72 Impact Factor
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    • "Transcriptional activity was analyzed with methods employed and validated in our previous research (Cole et al., 2003, 2005, 2011; Fredrickson et al., 2013; Miller et al., 2008). Briefly, raw data were quantile-normalized and log-2 transformed. "
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    ABSTRACT: Chronic stress is associated with morbidity and mortality from numerous conditions, many of whose pathogenesis involves persistent inflammation. Here, we examine how chronic stress influences signaling pathways that regulate inflammation in monocytes. The sample consisted of 33 adults caring for a family member with glioblastoma and 47 controls whose lives were free of major stressors. The subjects were assessed four times over eight months. Relative to controls, caregivers’ monocytes showed increased expression of genes bearing response elements for nuclear-factor kappa B, a key pro-inflammatory transcription factor. Simultaneously, caregivers showed reduced expression of genes with response elements for the glucocorticoid receptor, a transcription factor that conveys cortisol’s anti-inflammatory signals to monocytes. Transcript origin analyses revealed that CD14+/CD16􏰀 cells, a population of immature monocytes, were the predominate source of inflammatory gene expression among caregivers. We considered hormonal, molecular, and functional explanations for caregivers’ decreased glucocorticoid-mediated transcription. Across twelve days, the groups displayed similar diurnal cortisol profiles, suggesting that differential adrenocortical activity was not involved. Moreover, the groups’ monocytes expressed similar amounts of glucocorticoid receptor protein, suggesting that differential receptor availability was not involved. In ex vivo studies, subjects’ monocytes were stimulated with lipopolysaccharide, and caregivers showed greater production of the inflammatory cytokine interleukin-6 relative to controls. However, no group differences in functional glucocorticoid sensitivity were apparent; hydrocortisone was equally effective at inhibiting cytokine production in caregivers and controls. These findings may help shed light on the mechanisms through which caregiving increases vulnerability to inflammation-related diseases.
    Brain Behavior and Immunity 10/2014; 41(1):191-199. DOI:10.1016/j.bbi.2014.05.016 · 5.89 Impact Factor
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    • "Recent research in epigenetics has shown enduring molecular changes in response to early life adversity, but a biomarker reflecting such changes would still be difficult to definitively link with a specific event. Furthermore, a biomarker of exposure should be able to distinguish the effects of trauma exposure from the longterm alterations associated with chronic or severe stress (Miller, 2008). "
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    ABSTRACT: Although there are no established biomarkers for posttraumatic stress disorder (PTSD) as yet, biological investigations of PTSD have made progress identifying the pathophysiology of PTSD. Given the biological and clinical complexity of PTSD, it is increasingly unlikely that a single biomarker of disease will be identified. Rather, investigations will more likely identify different biomarkers that indicate the presence of clinically significant PTSD symptoms, associate with risk for PTSD following trauma exposure, and predict or identify recovery. While there has been much interest in PTSD biomarkers, there has been less discussion of their potential clinical applications, and of the social, legal, and ethical implications of such biomarkers.
    European Journal of Psychotraumatology 08/2014; 5. DOI:10.3402/ejpt.v5.23797 · 2.40 Impact Factor
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