Signals from the hypothalamus to the pituitary during chronic immune responses

Abstract

The question of whether stress is good or bad is a pertinent one in relation to pathology. A major component of the host response to stress is the activation of the hypothalamo-pituitary-adrenal (HPA) axis. The end point of this activation is the release of glucocorticoid steroid hormones from the adrenal cortex (predominantly corticosterone in the rat and cortisol in man). The importance of this system to the integrity of the individual can be demonstrated by investigating the extreme situation where the adrenal is removed or no longer functioning. This situation can be created surgically in experimental animals and occasionally in humans, although more frequently it occurs as a result of defective function of the adrenals due to autoimmune disease or tuberculosis leading to adrenal insufficiency (Addison’s disease). In patients with Addison’s disease minor challenges which might only produce mild symptoms in a normal individual can be life threatening. An interesting parallel to this can be seen following injection of the cytokine interleukin-1 (IL-1) or the immune stimulant lipopolysaccharide (LPS) an agent which produces flu-like symptoms for a few hours when given to humans. Doses which only result in “sickness behaviour” in adrenal-intact animals prove fatal in the absence of adrenal glands. In a number of animal models of immune-mediated diseases such as experimental allergic encephalomyelitis (EAE) and adjuvant-induced arthritis (AA) it has been demonstrated that in adrenalectomized animals following induction of the disease there is an earlier onset, an increased severity and, if left untreated, a fatal outcome. In all these cases treatment with steroids diminishes the severity of disease and prevents the fatal outcome. This chapter will draw together our current understanding of the mechanisms, particularly at the central level, underlying the activation of the HPA axis following immune activation. Much of our understanding of these mechanisms comes from studies in experimental animal models and this chapter will concentrate principally but not exclusively on the evidence from these.