Neuroendocrine Function and Chronic Inflammatory Stress

Abstract

The HPA axis and the response to acute stress The end-point of the activation of the HPA axis is the release of glucocorticoids (cortisol in man, corticosterone in rodents) from the adrenal cortex into the general circulation. The synthesis and release of glucocorticoids are controlled by ACTH released from the anterior pituitary gland. ACTH is synthesised from the precursor proopiomelanocortin (POMC) mRNA. The release of ACTH is regulated by the corticotrophin releasing factors corticotrophin-releasing factor(1-41) (CRF) and arginine vasopressin (AVP), which are released from the median eminence and synthesised in the parvocellular cells of the paraventricular nucleus (PVN). Under normal conditions approximately 50 % of these CRF neurons contain AVP; the remainder contain CRF but no vasopressin. CRF and AVP exert a synergistic action on the release of ACTH. The PVN acts as a co-ordinating centre receiving signals from many brain areas to regulate the response to stress. The glucocorticoids are able to regulate their own synthesis by negative feedback mediated by two corticosteroid receptors, the type II (glucocorticoid) receptor, which is found in the pituitary, PVN and other brain areas such as the hippocampus, and the type I receptor, which is found in the hippocampus. The hippocampus has a tonic inhibitory input to the PVN. In response to acute stress, the HPA axis is activated evoking the release of CRF and AVP into the The factors regulating susceptibility and severity of autoimmune diseases are poorly understood. That neuroendocrine factors are critical modulators in this regard is self-evident. For example, there are major gender differences in susceptibility with women at greater risk than men of, for example, rheumatoid arthritis (RA) and multiple sclerosis (MS). The hypothalamo-pituitary-adrenal (HPA) axis has rightly attracted a considerable amount of attention. Of particular interest has been the hypothesis that susceptibility to autoimmune disease may be related to an impaired responsiveness of the HPA axis; that is, an inability to mount an appropriate cortisol response with which to down-regulate the immune system might allow the immune system to rampage unchecked and attack self. This hypothesis links regulation of the release from the adrenal gland of the potent anti-inflammatory glucocorticoids to the disease process. Endogenous glucocorticoids are crucial for the regulation of the severity of the disease process. The hypothesis proposing a link between a hyporesponsive HPA axis and susceptibility to disease is compelling. However, evidence from a number of sources has suggested that this may not be the entire story and alterations in the activity of the HPA axis have not been consistently observed in patients with RA. This review will concentrate on recent findings concerning the HPA axis in determining susceptibility to, and in regulating the severity of, inflammatory processes in autoimmune disease. These studies have revealed that a single exposure to endotoxin can confer protection to sub...

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