Marvin Stein

Corticosterone regulation of Type I and Type II adrenal steroid receptors in brain, pituitary, and immune tissue

Type I and Type II adrenal steroid receptor levels were compared in the brain, pituitary and immune system of adrenalectomized rats in the presence or absence of several replacement doses of corticosterone. Six days of adrenalectomy produced an up-regulation of Type II adrenal steroid receptors in the brain and spleen. The lowest replacement dose of corticosterone (equivalent to resting levels of this hormone) blocked this Type II receptor up-regulation, while higher replacement doses of corticosterone were associated with widespread Type I and Type II adrenal steroid receptor down-regulation. However, the dose of corticosterone required for receptor down-regulation varied between tissues. Specifically, hippocampal receptors were most sensitive to corticosterone, whereas pituitary receptors were the least sensitive. All tissues examined, except the pituitary, exhibited a down-regulation of Type II receptors with a high corticosterone replacement dose which approximated acute stress levels of this hormone. In summary, physiologically relevant concentrations of corticosterone were capable of down-regulating Type I and Type II adrenal steroid receptors in multiple brain areas and peripheral immune tissues, including peripheral blood mononuclear cells. In contrast, adrenal steroid receptor levels in the pituitary were relatively insensitive to regulation by corticosterone.

Adrenal Steroid Receptor Activation in Rat Brain and Pituitary Following Dexamethasone: Implications for the Dexamethasone Suppression Test

The dexamethasone suppression test (DST) has been used extensively to evaluate feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) axis by adrenal steroids. Nevertheless, it remains unclear at what level of the HPA axis and through which adrenal steroid receptor subtype dexamethasone exerts its inhibitory effect. Because adrenal steroid receptor activation is an important prerequisite for dexamethasone to affect cellular function, HPA axis tissues that exhibit evidence of receptor activation following dexamethasone administration are likely site(s) of action for this synthetic hormone to inhibit HPA axis activity. Therefore, type-I and type-II adrenal steroid receptor activation was assessed in the pituitary, hypothalamus, and hippocampus of intact and adrenalectomized rats after overnight exposure to various oral doses of dexamethasone. Results with dexamethasone were compared to similar studies using corticosterone, the endogenous glucocorticoid of the rat. All dexamethasone doses led to significant type-II receptor activation in the pituitary, whereas only an exceedingly high dexamethasone dose activated type-II receptors in the hippocampus and hypothalamus. Dexamethasone had little effect on type I receptors in any tissue at any dose. In contrast, corticosterone significantly activated type-I receptors in all tissues, whereas it activated type-II receptors in the brain and not the pituitary at physiological concentrations. Because dexamethasone activated pituitary type-II receptors at blood concentrations that did not activate type-II receptors in the brain, these results suggest that the DST in humans may primarily be a measure of type-II adrenal steroid receptor feedback inhibition at the level of the pituitary.

Suppression of lymphocyte stimulation by anterior hypothalamic lesions in the guinea pig.

Abstract Anterior hypothalamic lesions in the guinea pig inhibited lymphocyte stimulation in whole blood cultures with the antigen tuberculin and with the mitogen phytohemagglutinin (PHA) and suppressed the delayed cutaneous hypersensitivity response to tuberculin. The lesions did not affect the stimulation of purified lymphocytes with either tuberculin or PHA. The anterior hypothalamic lesions had no effect on the absolute number of T and B lymphocytes.

Depression, Adrenal Steroids, and the Immune System

During the past decade, over 30 studies have examined the immune system in depression. While a number of investigators have reported depression-related alterations in peripheral blood immune cell number and function, many researchers have been unable to replicate these findings. The relationship between depression and the immune system has turned out to be much more complex than was initially anticipated. Factors which have complicated the interpretation of the research include the heterogeneity of depressed patients, the variability of immune assays, and the clinical relevance of these assays. In this review we conclude that alterations in the immune system do not appear to be a specific or reproducible biological correlate of depression but may occur in association with other variables which characterize depressed patients including age, sex and severity of depression. Conceptual frameworks for future research on the immune system and depression are discussed and include: (i) depression as a cofactor in the development, course and outcome of diseases involving the immune system; (ii) depression as a neuroimmunological disease; and (iii) depression as a model for studying neuroendocrine-immune interactions in humans. In terms of this third line of research, patients with depression consistently have been shown to display abnormalities in the secretion of adrenal steroids, and new data is presented which indicates that adrenal steroids may play a much more complex role in the modulation of the immune response than has been previously appreciated.

Depression and the Immune System

Publisher Summary This chapter discusses the effects of depression on immune system. Neuroimmunology primarily concerns itself with disordered immune function that affects the nervous system and alters the central nervous system activity. This field of study encompasses autoimmune and viral processes associated with neurologic and/or systemic diseases that may manifest behavioral pathology and/or neuropsychological impairments as can be observed in multiple sclerosis and systemic lupus erythematous. The immune system in depression may be viewed from the perspective of the role of immune function in the maintenance of health and the development of physical disease. The relationship between depression and cancer is complex and may be related to a variety of factors. In some instances, depression may be a manifestation of a cerebral metastasis that has not produced any physical symptoms or may be a nonmetastatic symptom of an undetected cancer. Cancer of the pancreas is well-known to manifest initially with depressive symptoms. There has been increasing interest in the possible therapeutic value of treating depression and thereby influencing the immune system, with consequent health implications.

Premature maternal separation and lymphocyte function

Premature separation of rat pups from their mothers, on postnatal Day 15, produced a decreased response of peripheral blood lymphocytes to phytohemagglutinin (PHA) at 40 days of age. A significant lymphopenia was also found in the early weaned animals at 40 days of age although this was accounted for statistically by their lower body weight. These consequences of early maternal separation may have been mediated through the effects of early separation on nutritional state, hypothalamic function, or maturation of the immune system.

Behavioral and Developmental Aspects of Immunity

Considerable evidence is accumulating which demonstrates a relationship between immune function and behavioral states such as object loss or depression. Findings have been described using animal and clinical models, and a complex chain of biological and psychological processes may be involved. Further research on behavioral, central nervous system, and immune interactions in childhood is needed and is especially important since the developing immune system may be particularly susceptible to behavioral effects. Effects on the immune system in early life may have profound long-term effects on immune capacity.

Stress, the Hypothalamic-Pituitary-Adrenal Axis, and Immune Function

A variety of Stressors have been shown to alter both humoral and cell-mediated immune responses. Over the past decade the pathways by which stress may influence the immune system has been the focus of intense study. One of the most important pathways is the hypothalamic-pituitary-adrenal (HPA) axis (1, 2). It has been known for some time that glucocorticoids, the final product of HPA axis activation, have a wide range of effects on immune and inflammatory responses in humans and animals. In addition, other HPA hormones such as corticotropin releasing hormone (CRH) and corticotropin (ACTH) can directly and indirectly influence immune function.

A simplified method for assessing PHA induced stimulation of rat peripheral blood lymphocytes

Abstract A simple micro-method is described for assaying lymphocyte stimulation in the rat. This method utilizes Percoll as the density gradient, fetal calf serum as the medium supplement and [ 125 I]UdR/FUdR as the label. The technique provides a simple and rapid assay of lymphocyte stimulation of rat peripheral blood lymphocytes.

Immune System: Relationship to Anxiety Disorders

The demonstration that behavioral states and CNS processes are associated with immune function suggests that there may be a relationship between anxiety and the immune system. Stress and immunity have been studied extensively, but there have been relatively few studies of anxiety and immunity. Many of the neurobiologic processes associated with stress and with depression have been observed in anxiety and are known to influence the immune system. A review of the immune response to stress and of immune alterations in depression has been presented in an effort to provide further understanding of the biology of anxiety. It appears that a variety of factors such as age; sex; nature, intensity, and chronicity of a stressful life events; and psychologic response to life stress need to be considered in the investigation of behavior and immunity. The biologic effects of stress on immunity are multifaceted, including complex neuroendocrine and neurotransmitter interactions. Further investigation is required of anxiety and immunity in clearly delineated and diagnosed anxiety states and disorders. Such studies may help to elucidate the pathophysiology of anxiety disorders.