New Aspects of the Immunoregulation by the Hypothalamo-Pituitary-Adrenal (HPA) Axis

One of the basic neuro-immune-endocrine interaction is the hypothalamo-pituitary-adrenal axis (HPA) to harmonize immune response to inflammatory stressors. Immune defense mechanisms mediated by cytokines and other humoral factors play particularly important roles in this communication. They are also potent activators in the CNS and factors of the HPA axis, like an increased secretion of glucocorticoids (GC). They can act as major feedback regulator of the vertebrate immune response via suppression of a wide range of cytokines, as well as interferons. Increases in systemic GC levels, however, often play dual role: do not suppress all cytokines since inhibition of a particular cytokine may result in elevated production of others. External stimuli/acute stress can compromise activation of the HPA axis and activate immune processes for defense, redirecting leukocytes from the circulation to the environment/organism interface. Overall it results in release of danger-associated molecular patterns (DAMPs) to activate cells of the innate immune system, which is resolved by neural, hormonal or immune mechanisms. The chronic stress leads to chronic immune arousal and subsequent sterile, low-grade inflammation, which has been identified in most “stress-related or “civilized” disorders in humans. The role of pituitary-gonadal axis in the activation of HPA axis results in a gender difference in HPA response to immunological challenges: e.g. can be varied during the estrus cycle, pregnancy or lactation. That corresponds to the results of recent experimental data that reveals an important role of certain neurotramsitters (such as dopamine) in immune regulation. Internal constitutional-factors of neuro-immune-endocrine interaction, such as corticotropin-releasing hormone (CRH) and its receptors (CRF-R1 and CRF-R2), melanocortin peptides, glucocorticoids or pro-inflammatory cytokines can also act as an immunoregulator, since their receptors is present in lymphoid organs, also in peripheral blood and organs that are enhanced under inflammatory conditions. In spite of series experimental data, the role of CRH and other members of its family, as well as its receptors in inflammation are still controversial. This dual role may be due to different CRF receptors and altered functionality. There are several putative mechanisms or “ports of entry”, in which the cytokines may affect HPA activity and CRH release. Some influences of cytokines on the HPA axis may be exerted by an indirect way. The aim of our review was to summarize and outline of key interacting agents based upon recent experimental results.