Marni N. Silverman

Glucocorticoid Dysregulations and Their Clinical Correlates: From Receptors to Therapeutics

Clinicians have long known that a substantial proportion of patients treated with high‐dose glucocorticoids experience a variety of serious side effects, including metabolic syndrome, bone loss, and mood shifts, such as depressive symptomatology, manic or hypomanic symptoms, and even suicide. The reason for individual variability in expression or severity of these side effects is not clear. However, recent emerging literature is beginning to shed light on possible mechanisms of these effects. As an introduction to this volume, this chapter will review the basic biology of glucocorticoid release and molecular mechanisms of glucocorticoid receptor function, and will discuss how dysregulation of glucocorticoid action at all levels could contribute to such side effects. At the molecular level, glucocorticoid receptor polymorphisms may be associated either with receptor hypofunction or hyperfunction and could thus contribute to differential individual sensitivity to the effects of glucocorticoid treatment. Numerous factors regulate hypothalamic‐pituitary‐adrenal (HPA) axis responsiveness, which could also contribute to individual differences in glucocorticoid side effects. One of these is sex hormone status and the influence of estrogen and progesterone on HPA axis function and mood. Another is immune system activity, in which immune molecules, such as interleukins and cytokines, activate the HPA axis and alter brain function, including memory, cognition, and mood. The effects of cytokines in inducing sickness behaviors, which overlap with depressive symptomatology, could also contribute to individual differences in such symptomatology. Taken together, this knowledge will have important relevance for identifying at‐risk patients to avoid or minimize such side effects when they are treated with glucocorticoids. A framework for assessment of patients is proposed that incorporates functional, physiological, and molecular biomarkers to identify subgroups of patients at risk for depressive symptomatology associated with glucocorticoid treatment, and for prevention of side effects, which in many cases can be life‐threatening.

Elevated Neuroimmune Biomarkers in Sweat Patches and Plasma of Premenopausal Women with Major Depressive Disorder in Remission : The POWER Study

BACKGROUND Major depressive disorder (MDD) is inconsistently associated with elevations in proinflammatory cytokines and neuropeptides. We used a skin sweat patch, recently validated in healthy control subjects, and recycling immunoaffinity chromatography to measure neuroimmune biomarkers in patients with MDD mostly in remission. METHODS We collected blood at 8:00 am and applied skin sweat patches for 24 hours in 21- to 45-year-old premenopausal women (n = 19) with MDD (17/19 in remission) and age-matched healthy controls (n = 17) participating in the POWER (Premenopausal, Osteopenia/Osteoporosis, Women, Alendronate, Depression) Study. RESULTS Proinflammatory cytokines, neuropeptide Y, substance P, and calcitonin-gene-related peptide were significantly higher and vasoactive intestinal peptide, a marker of parasympathetic activity, was significantly lower in patients compared to controls, and depressive symptomatology strongly correlated with biomarker levels. All analytes were strongly correlated in the skin sweat patch and plasma in patients (r = .73 to .99; p < .0004). CONCLUSIONS The skin sweat patch allows detection of disrupted patterns of proinflammatory cytokines and neuropeptides in women with MDD in clinical remission, which could predispose to medical consequences such as cardiovascular disease, osteoporosis, and diabetes. This method permits measurement of cytokines in ambulatory settings where blood collection is not feasible.

Neuroendocrine and Immune Contributors to Fatigue

Central fatigue, a persistent and subjective sense of tiredness, generally correlates poorly with traditional markers of disease. It is frequently associated with psychosocial factors, such as depression, sleep disorder, anxiety, and coping style, which suggest that dysregulation of the bodys stress systems may serve as an underlying mechanism in the maintenance of chronic fatigue (CF). This article addresses the endocrine, neural, and immune factors that contribute to fatigue and describes research regarding the role of these factors in chronic fatigue syndrome as a model for addressing the biology of CF. In general, hypoactivity of the hypothalamic‐pituitary‐adrenal axis, autonomic nervous system alterations characterized by sympathetic overactivity and low vagal tone, as well as immune abnormalities, may contribute to the expression of CF. Noninvasive methods for evaluating endocrine, neural, and immune function are also discussed. Simultaneous evaluation of neuroendocrine and immune systems with noninvasive techniques will help elucidate the underlying interactions of these systems, their role in disease susceptibility, and progression of stress‐related disorders.

Evaluation of stress systems by applying noninvasive methodologies: measurements of neuroimmune biomarkers in the sweat, heart rate variability and salivary cortisol.

The two main arms of the stress system include the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal (HPA) axis. These two neural stress systems coordinate the response of many other physiological systems to a stressor, including the immune and cardiovascular systems, bringing the body back to homeostasis. The nervous and immune systems communicate with each other in a bidirectional manner. In this review, we will discuss the use of noninvasive methods to evaluate the immune system, ANS and HPA axis. Collection of sweat and saliva, and measurement of heart rate variability are noninvasive methods that can be applied to evaluate neuroimmune interactions. Recently, we validated a new methodology to simultaneously evaluate a large array of neural and immune biomarkers in sweat, collected through cutaneous sweat patches and measured by recycling immunoaffinity chromatography. Noninvasive and ambulatory methodologies of biomarker collection can overcome several limitations intrinsic to invasive methods, such as reducing the stress triggered by collection itself and allowing a wider application to field and community-based settings. Ultimately, simultaneous evaluation of neural and immune systems with noninvasive techniques will help elucidate the underlying interactions of these systems and their role in disease susceptibility and progression of stress-related disorders.

Neuroendocrine-Immune Interactions in Rheumatoid Arthritis: Mechanisms of Glucocorticoid Resistance

Rheumatoid arthritis (RA) is characterized by chronic inflammation of the synovial membrane, leading to joint destruction. Many autoimmune diseases and disease states of chronic inflammation are accompanied by alterations in the complex interactions between the endocrine, nervous and immune systems. Glucocorticoids, an end product of the hypothalamic-pituitary-adrenal axis, are a mainstay treatment for many autoimmune diseases, including RA, because of their potent anti-inflammatory action. However, about 30% of patients with RA fail to respond to steroid therapy. There are various mechanisms that may contribute to the development of glucocorticoid resistance in inflammatory disorders, which will be the subject of this review. In addition, glucocorticoid resistance may be a contributing factor in the development of inflammatory/autoimmune diseases themselves. Therefore, further elucidation of these mechanisms will reveal new targets for therapeutic intervention in the treatment of RA.

Glucocorticoid regulation of inflammation and its behavioral and metabolic correlates: from HPA axis to glucocorticoid receptor dysfunction

Enhanced susceptibility to inflammatory and autoimmune disease can be related to impairments in HPA axis activity and associated hypocortisolism, or to glucocorticoid resistance resulting from impairments in local factors affecting glucocorticoid availability and function, including the glucocorticoid receptor (GR). The enhanced inflammation and hypercortisolism that typically characterize stress‐related illnesses, such as depression, metabolic syndrome, cardiovascular disease, or osteoporosis, may also be related to increased glucocorticoid resistance. This review focuses on impaired GR function as a molecular mechanism of glucocorticoid resistance. Both genetic and environmental factors can contribute to impaired GR function. The evidence that glucocorticoid resistance can be environmentally induced has important implications for management of stress‐related inflammatory illnesses and underscores the importance of prevention and management of chronic stress. The simultaneous assessment of neural, endocrine, and immune biomarkers through various noninvasive methods will also be discussed.

Matching therapy to body rhythms: an endocrine approach to treating rheumatoid arthritis.

The value and efficacy of corticosteroids in treatment of rheumatoid arthritis (RA) has been recognized ever since the Nobel Prize in Physiology and Medicine was awarded in 1950 for the astonishing discovery of Edward Kendall, Philip Hench, and Tadeus Reichstein1. The description of Hench’s treatment of the first patient with Kendall’s compound E (later known as cortisone) reads like a story out of the annals of the miracle cures at Lourdes2. The young woman, unable to walk and bedridden with severe debilitating RA for 4 years, gets up, walks and leaves hospital recovered, only 4 days after treatment with daily intramuscular injections of the drug. The Nobel Prize was awarded to this team only one year after this observation, and after treatment of another couple of dozen patients3. Prednisone has since been a mainstay of treatment of RA and other inflammatory/autoimmune conditions. The major stumbling block for this otherwise miraculous drug has been its severe side effects when used in high doses and for prolonged periods of time. These include adrenal insufficiency; osteoporosis; metabolic syndrome, including diabetes; central fat deposition; skin atrophy; “moon” face; impaired resistance to infection, with increased … Address correspondence to Dr. Sternberg. E-mail: sternbee{at}mail.nih.gov

Glucocorticoid regulation of inflammation and its functional correlates: from HPA axis to glucocorticoid receptor dysfunction: Glucocorticoid resistance in inflammatory disease

Enhanced susceptibility to inflammatory and autoimmune disease can be related to impairments in HPA axis activity and associated hypocortisolism, or to glucocorticoid resistance resulting from impairments in local factors affecting glucocorticoid availability and function, including the glucocorticoid receptor (GR). The enhanced inflammation and hypercortisolism that typically characterize stress‐related illnesses, such as depression, metabolic syndrome, cardiovascular disease, or osteoporosis, may also be related to increased glucocorticoid resistance. This review focuses on impaired GR function as a molecular mechanism of glucocorticoid resistance. Both genetic and environmental factors can contribute to impaired GR function. The evidence that glucocorticoid resistance can be environmentally induced has important implications for management of stress‐related inflammatory illnesses and underscores the importance of prevention and management of chronic stress. The simultaneous assessment of neural, endocrine, and immune biomarkers through various noninvasive methods will also be discussed.

Impaired glucocorticoid receptor dimerization exacerbates LPS-induced sickness behavior and inflammation in mice

zations and natural antigen exposure prior to pregnancy. To determine if immune memory influences development of offspring in a murine model of maternal immune stimulation, C57BL/6 (B6) female mice were immunized with allogeneic female Balb/c spleen cells. Immune and immunologically naı̈ve wild-type (WT) B6 and IL-6 KO females were mated with WT B6 males and injected i.p. with PBS or poly(I:C) on gestational day 12. Higher levels of IL-6 were seen in maternal sera and amniotic fluids of immune vs naı̈ve poly(I:C)-injected WT dams. However, in matings between IL-6 KO (IL-6 / ) females and WT (IL-6+/+) B6 males, significantly higher levels of IL-6 were found in amniotic fluids. Analysis of supernatants from cultured placental cell preparations revealed significant IL-6 production from the heterozygous (IL-6+/ ) fetal component. Splenocytes from immune (vs. naı̈ve) WT B6 pregnant females also showed higher proliferative responses to the CD4+ T cell restricted epitope of a male H-Y-encoded antigen. Moreover, FACS analysis of activated spleen cells from offspring of immune (vs. naı̈ve) poly(I:C)-injected WT dams showed >fivefold increase in Th17 cells. These results indicate that immune stimulation during pregnancy in females with immunological memory leads to development of a Th17 cell repertoire in offspring, which could mediate immunopathology similar to that reported in mouse models of human autoimmune diseases (e.g., EAE, RA, IBD).

79. The effects of the physical work environment on circadian variations in heart rate variability

in cytokines and mood. Sixty healthy men took part in a double-blind study. Trait optimism was assessed by the Life Orientation Test. Participants received typhoid vaccine or saline placebo. Thirty minutes post-injection, they either rested or completed two challenging tasks; colour/word and public speaking, at the end of which they rested for a further 2 h. Ratings of mood were obtained using the Profile of Mood States at baseline, immediately after tasks and during recovery. Tasks induced a significant increase in circulating levels of IL-6 and negative mood. The mood eect was significantly more marked in participants who had received typhoid vaccine versus placebo. The IL-6 response was also larger in the vaccine versus placebo group, although the eect was not significant. Optimists had significantly smaller IL-6 responses to stress, and smaller increases in anxiety and negative mood compared to less optimistic individuals. There were no significant changes in mood or cytokines in the non-stress control group. Taken together, these results suggest that optimism may protect against negative mood responses to psychological and immune stressors, potentially through modulating inflammatory cytokines.