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The role of adrenocorticoids as modulators of immune function in health and disease: neural, endocrine and immune interactions

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Introduction

Glucocorticoids are powerful regulators of immune function. Their role in reducing inflammation and autoimmune responses is well known, as is their ability to induce apoptosis in immature thymocytes. However, much of the story of glucocorticoid effects on immunity has been derived from in vitro studies on immune cells, as well as from the in vitro and in vivo actions of synthetic glucocorticoids, both of which may not represent the complex effects manifested by endogenous adrenal steroids in vivo. As a result, the picture of glucocorticoid actions on immune function has been biased towards the immunosuppressive actions of these hormones. A more accurate view of endogenous glucocorticoids is that they are subtle and complex modulators of immune function, not only containing the exuberance of inflammatory and autoimmune responses, but also both enhancing and inhibiting host immune responses and thereby influencing disease susceptibility and progression.

This article will summarize our current knowledge of glucocorticoid physiology in relation to immune function in health and disease. This is an important task because, while glucocorticoids are powerful regulators of immune function, much of the work on this topic has been fragmentary with regard to the specificity and diversity of glucocorticoid actions within diverse immune cell types and organs. As will be seen, the distribution of adrenal steroid receptors is different among immune cell types; and so are the effects of adrenal steroids on the response to or production of immune modulators. Finally, all of this must be viewed in the context of disease, in order to determine the range of glucocorticoid effects that are beneficial to the host response during an immune challenge and to ascertain the levels of stress or exposure to glucocorticoids that exacerbate disease processess.

In his Nobel Lecture delivered in 1950, Philip Hench [197]described the discovery of an endogenously derived substance which had a significant impact on disease expression in individuals suffering from rheumatoid arthritis [197]. His work stemmed from clinical observations that a variety of concurrent conditions including jaundice, pregnancy, typhoid vaccination, surgical operations and short periods of starvation could significantly alter the course of rheumatoid arthritis and other immunologic disorders such as hay fever and asthma. Ultimately, he developed the idea that the concurrent conditions somehow stimulated the release of an endogenous substance which was both anti-allergic as well as anti-rheumatic. Discovery that the endogenous compound was the adrenal steroid, cortisone (Kendall's Compound E or 17-hydroxy-11-dehydrocorticosterone), ushered in the era of glucocorticoid therapy as a cornerstone of the treatment of autoimmune and inflammatory diseases. Since Hench's discovery [197], tremendous strides have been made regarding the clinical use of adrenal steroids. Moreover, numerous studies have revealed the basic biochemical and molecular mechanisms by which adrenal steroids influence specific immune responses.

Concurrent with the early work of Hench and Kendall, Hans Selye [393]introduced experimental data demonstrating that a wide variety of stressors were associated with enlarged adrenal glands and involution of the thymus, providing an important connection between endogenous hormones and the immune system. However, Selye believed that glucocorticoids enhanced disease resistance by, for example, lysing lymphocytes and releasing antibodies [394]. He suggested that rheumatoid arthritis might be a disorder caused by an overproduction of adrenocortical hormones during stress and therefore represented a disease of adaptation. When the anti-inflammatory and immunosuppressive effects of glucocorticoids were discovered in the late 1940s, Selye's notion of glucocorticoid enhancement of immune system function was abandoned.

In an effort to resolve the contrasting roles of glucocorticoids as both critical facilitators of the adaptive response to stress and powerful immunosuppresive agents, it was suggested that the inhibitory effects on immune function were primarily a result of pharmacologic effects of these hormones whereas the more positive effects of glucocorticoids in orchestrating the adaptive response to stress were physiologic in nature. A decade ago, based on work that all effects of adrenal steroids, whether occuring at physiologic or pharmacologic concentrations, were mediated through the glucocorticoid receptor, a new model for glucocorticoid–immune interactions was proposed. Incorporating the anti-inflammatory and immunosuppressive effects of glucocorticoids, Alan Munck suggested that adrenal steroids were functioning to protect the body by preventing or `containing' a potential overshoot of immune responses 327, 328: e.g., containing or preventing immunologic responses to `self' antigens released during tissue damage that would cause further tissue injury and possibly the development of autoimmune disorders. These notions of glucocorticoid containment of the immune system were further developed by Hugo Besedovsky who suggested that glucocorticoid elevations following administration of non-specific immune activators represented the role of endogenous glucocorticoids in fine-tuning immune responses, antigen–antibody interactions in particular, after an immune challenge [40]. Munck presented the containment of the immune response in the broader context of glucocorticoid containment of a host of other physiological responses, ranging from edema after trauma to neurochemical responses to stressors [328]. This notion has been further developed for the brain and provides a basis for understanding how neural and behavioral responses to stressful challenges are buffered and regulated by the same agents which contain immune function [295].

More recently, it has become apparent that glucocorticoids, as originally suggested by Selye, do enhance certain aspects of the response to an immune challenge. Therefore, considerable interest has been shown in developing alternative models of glucocorticoid–immune interactions that incorporate both the facilitative as well as the inhibitory effects of endogenous glucocorticoids 29, 110, 220, 481. In other words, models are needed wherein glucocorticoids guide and shape the immune system rather than either enhance or contain immune responses. The data upon which such a revision might be based is the topic of this review.

Section snippets

Components of the neuroendocrine-immune axis

The tissues and organs of the immune system are innervated by the autonomic nervous system (ANS) and bathed by endocrine and paracrine hormones. They are dynamic structures which develop and mature under the influence of these hormonal and neural regulators, in addition to their own internal regulators, cytokines. In order to understand the immunologic influence of glucocorticoids, it is necessary to understand something about the organization of the immune system, its function and its

Behavior and individual differences

Before considering the role of glucocorticoids in detail, we shall summarize what is known about behavioral influences on immune function and consider the influence of stressful events on immunity. It is important to discuss stress effects on immunity as an initial reference point because stressful experience are not simply mimicked by elevating stress hormone levels, as will be discussed later in this review. Indeed, many stressors activate autonomic and HPA activity as well as behavioral

Mechanisms of action of adrenal steroids on the immune system

Whereas there are multiple regulators of immune function, it is the actions of adrenal steroids that are among the most powerful and pervasive, as well as somewhat misunderstood. In general, many of the adrenal steroid effects involve inhibition of immune function, but in quite a few instances glucocorticoids may actually enhance both the availability and activity of specific immune cells (see Table 1). We now consider the receptors for adrenal steroids and their actions on immune cells and

Disease models

The only way to see how effectively the immune system works in the living organism is to challenge it with a pathogen or tumor or to observe how it operates during inflammatory or autoimmune states. This is particularly important for understanding the role of adrenal steroids and other hormonal and neural modulators of immunity. In the following section, we will consider glucocorticoid actions in relation to viral infections, tumors, and inflammatory and autoimmune conditions.

A new view of adrenal steroid effects on immune function

In this article, we have summarized many aspects of glucocorticoid actions on the immune response; and we have emphasized the physiological role that adrenal steroids play as modulators of the immune system, in contrast to the more traditional view of glucocorticoids as immunosuppressors.

First, it is clear that the endogenous glucocorticoids have far more limited access to adrenal steroid receptors in immune tissues than synthetic glucocorticoids and that the actions of synthetic

Acknowledgements

This work was supported by the John D. and Catherine T. MacArthur Foundation Health Program and the Health and Behavior Network (Judith Rodin, Chair, and Grace Castellazzo, Administrator).

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    Present address: Department of Psychology, University of Colorado, Boulder, CO, USA.

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