FIFTEENTH GADDUM MEMORIAL LECTURE DECEMBER 1994 Stress and the neuroendocrine‐immune axis: the pivotal role of glucocorticoids and lipocortin 1

Widespread evidence now supports the view that reciprocal communication between the brain-endocrine system and the immune system is fundamental to host defence processes in conditions of health and disease. Importantly, it provides a means whereby the central nervous system can detect alterations in immune status (e.g. infections) and initiate a co-ordinated series of responses (immunological, metabolic, physical, behavioural) which is designed specfically to protect the host and thus to restore homeostasis. Several paths of communication between the two systems have been identified. These include firstly neural links provided by the afferent/efferent autonomic fibres (predominantly sympathetic) which connect the lymphoid organs and tissue with the brain and secondly humoral transmission which is effected by hormones released from the pituitary gland and peripheral endocrine organs and by mediators (termed immunokines) released from activated immune/inflammatory cells. In addition, since immune insults initiate the synthesis of immunokines in the neuroendocrine system while causing lymphoid cells/tissues to produce 'neuroendocrine peptides' such as corticotrophin (ACTH), there is opportunity for a degree of local interplay between the two systems. Many peptide and steroid hormones have been implicated in the processes of neuroendocrine-immune communication. The bulk of attention however has focused on the hypothalamo-pituitary-adrenocortical (HPA) axis largely because its end products, the glucocorticoids, have a well established role in the control ofimmune/inflammatory cell function (reviewed in Munck et al., 1984; Munck & Naray-Fejes-Toth 1994; Munck & Gyre, 1991). The HPA axis provides an essential interface between the internal and external environment and enables the organism to adapt to diverse noxious stimuli, whether they be cognitive (e.g. emotional or physical trauma) or non-cognitive (e.g. immune insults). It is promptly activated in conditions of stress and the substantial quantities of glucocorticoids released into the systemic circulation serve to restore homeostasis through multiple mechanisms which include modulation of immune/ inflammatory responses. Failure to mount an appropriate adrenocortical response in conditions of stress is potentially hazardous and indeed disturbances in HPA function are now considered to be a significant contributory factor in the aetiology of a variety of disease processes. For example, excessive glucocorticoid secretion (which may arise from a primary disorder of the HPA axis or from causes as diverse as e.g. ectopic ACTH producing tumours, depression, stress, alcoholism, anorexia) causes diverse metabolic and behavioural disturbances together with immunosuppression which, in turn, may predispose the individual to other disease processes, e.g. infections, cancer. Conversely, adrenocortical insufficiency (which may reflect primary or secondary adrenal failure or steroid resistance in the target tissues) precipitates a vulnerability to stress and is increasingly implicated in the pathogenesis of autoimmune, inflammatory and allergic disorders (e.g. rheumatoid arthritis, multiple sclerosis, systemic lupus erythematous, reviewed in Derjik & Sternberg, 1994). In healthy individuals, the serum glucocorticoid concentrations are maintained within narrow limits with overt excursions occurring only in accord with the well established carcadian rhythm and in response to stressful stimuli. Critical to this tight control is a complex servo mechanism through which the glucocorticoids negatively regulate their own secretion and thus effectively contain the adrenocortical responses to incoming stimuli (e.g. stress) within appropriate limits. This article, which is dedicated to the memory of the late J.H. Gaddum, will discuss the molecular mechanisms underlying the pivotal feedback actions of the glucocorticoids within the HPA axis, focusing on our recent studies which identify a fundamental role for lipocortin 1 (LC1) as a mediator of glucocorticoid action in the neuroendocrine system. A brief review of the mechanisms by which stressors activate the HPA axis precedes this discussion.