The HPA Axis and the Immune System: A Perspective

Abstract Although it had long been known that steroids secreted by the adrenal cortex exerted important inhibitory effects on cells of the immune system, the concept of bidirectional communication between the immune system and the nervous system became widely accepted when it was recognized that activation of the hypothalamo–pituitary–adrenocortical (HPA) axis associated with stress was not the only effect the central nervous system (CNS) exerted on the immune system, and that factors secreted by immune cells could have important effects on the CNS. Activation of the HPA axis results in elevation of circulating concentrations of corticosteroids which drive them from the thymus and spleen into the periphery and inhibit various immune activities. The immune system can also signal the CNS regarding the presence of foreign antigens in peripheral organs. A key finding was that interleukin-1 (IL-1) was a potent stimulator of HPA axis activity. The major known mechanism by which the immune system signals the brain involves cytokines, which are the major chemical messengers within the immune system. Certain other cytokines [e.g, IL-6, IL-10, and tumor necrosis factor-α (TNF-α)] can activate the HPA axis. Cytokines exert their effects on the CNS via afferents of nerves, such as the vagus, although some direct actions of circulating cytokines on the nervous system may also occur. Immune cells can penetrate the brain under some circumstances. The CNS in turn can influence immune function via the autonomic nervous system and various hormones secreted by the pituitary, the adrenal, and other endocrine organs. Cytokines (especially IL-1) can alter the activity of neurotransmitters in the CNS, most notably norepinephrine and corticotropin-releasing factor (CRF), and can have important effects on behavior.