Comments on some clinical implications of the release of adrenocorticotropin and vasopressin by interleukin-6 and other cytokines.

The inflammatory cytokines [tumor necrosis factor-a, interleukin-1 (IL-l), and IL-61 cause the release of arginine vasopressin (AVP) and ACTH in viva and in vitro in animal studies (l-4). Current evidence now demonstrates that IL-6 is capable of releasing the two pituitary hormones in man (5, 6). Animal studies support a hypothalamic locus for these actions (4). This has not yet been demonstrated in man. These observations are part of a larger area of neuroendocrine-immune interactions recently described in some detail by Reichlin (7) and have important implications regarding the possible mechanism by which inflammatory processes increase the release of AVP and ACTH. The excessive release of AVP from inflammatory processes may result in the syndrome of inappropriate antidiuresis (SIADH). In contrast, the increased release of ACTH does not cause Cushing’s syndrome, but constitutes an appropriate physiological response to stress. In addition, the possibility now exists that hormonal responses to the injection of one of the inflammatory cytokines, probably IL-6, may be of value in the functional testing of AVP and ACTH secretory capacity. The administration of IL-6 in man is quite feasible, because unlike the severe toxic effects induced by tumor necrosis factor-a and IL-l, IL-6 stimulates AVP and ACTH release in man with modest toxicity and no hypotensive effect (5, 6). More than 60 yr ago, physicians became aware that pulmonary infections, particularly lobar pneumonia, could be associated with chloride depletion associated with urinary wastage of salt (8,9). Subsequently, SIADH was recognized as the cause of the hyponatremia and hypochloremia that occur in such conditions as bacterial and viral pneumonias, tuberculosis, pulmonary abscesses, and empyema (1 O-l 2). The same electrolyte changes and cause were recognized in patients with inflammatory disorders of the central nervous system, such as acute encephalitis, tuberculous, meningitis, and purulent meningitis (13). The possibility now exists that cytokine production from these lesions may, by autocrine, paracrine, or endocrine actions, stimulate excessive release of AVP without appropriately reducing fluid intake, thus resulting in the hyponatremia and hypochloremia of SIADH. As many tumors and tumor cell lines appear capable of producing IL-6 (14), SIADH in patients with malignancy may also result from the production and action of IL-6. With these possibilities in mind, efforts to develop effective therapeutic modalities for patients with SIADH due to inflam-