Adrenocorticotropin--a central trigger in immune responsiveness: tonal inhibition of immune activation

Adrenocorticotropin is known for its key role in mediating neuroendocrine responses, especially in response to stress. Recently, it has been recognized to have direct immunomodulatory actions, most of which are suppressive. This is a widely conserved action which occurs in invertebrates and vertebrates. This conservation illustrates the fundamental nature of adrenocorticotropin's immunomodulatory action. Such a mechanism of action helps explain why the immunocytes themselves can serve as a source of adrenocorticotropin. Regulation of adrenocorticotropin production and action is complex and the result is an integration of multiple mechanisms. Serum adrenocorticotropin levels fluctuate in response to stimulatory and inhibitory factors. Further, peptidases can specifically process adrenocorticotropin into smaller active fragments, inactive peptides or into peptides with different activities. These proteolytic enzymes have a differential tissue and cellular distribution. Immune stimulating factors such as interleukin-1 can overcome adrenocorticotropin inhibition and secondarily, block adrenocorticotropin production through the release of corticosteroids. With an endogenous presence and complex regulation it has been difficult to characterize adrenocorticotropin's role in the immune system. Here, we propose that adrenocorticotropin is a tonis regulator of immune response, i.e. it tonally inhibits immunocytes which undergo disinhibition as the result of exposure to stimulatory signals, e.g. cytokines, neuropeptides, etc. Thus, adrenocorticotropin appears to set the threshold for immunoactivation by controlling the degree of immunoexcitability.