EFFECTS OF CYTOKINES ON THE PITUITARY-ADRENAL AXIS IN CANCER-PATIENTS

Cytokines, which include interferons (IFNs), interleukins (ILs), and t umor necrosis factor (TNF), are immunoregulatory proteins produced by lymphocytes and inflammatory cells. Several cytokines, most noteworthy IFNs and ILs, stimulate glucocorticoid secretion. In this study, the effects of variable doses and repetitive administration of IFNs and TN F on secretion of pituitary hormones and cortisol were measured. Patie nts were given for a period of 15 days on alternating days injections of IFN-beta (IFN-beta(ser)), 90 or 450 x 10(6) IU, IFN-gamma, 0.1-100 x 10(6) IU, or TNF 125-275 mug/m2. Sixty to 120 min after IFN-beta(ser ) injection median levels of cortisol, adrenocorticotropin (ACTH), pro lactin (PRL), and growth hormone (GH) rose two-fold. Urinary free cort isol excretion increased significantly during the day following IFN-be ta(ser) administration. IFN-gamma greater-than-or-equal-to 30 x 10(6) IU caused a comparable rise in plasma cortisol. TNF induced two- to fo ur-fold increases in ACTH and cortisol. The fact that increased cortis ol secretion was associated with a rise in the level of ACTH as well a s PRL and GH suggests that the cytokines increased cortisol by stimula ting the anterior pituitary. The hormonal response induced by cytokine s was unrelated to their pyrogenic effect, undiminished with repetitiv e treatment, and not dose-dependent above a threshold level. These obs ervations reinforce the concept of a physiologic link between the immu ne system and the hypothalamic-pituitary-adrenal (HPA) axis.