Intracerebroventricular injection of interleukin-1 suppresses peripheral lymphocyte function in the primate

The cytokine interleukin-1 (IL-1) can act within the brain to induce peripheral endocrine and immune effects. In the rodent intracerebroventricular (i.c.v.) injection of IL-1 activates the hypothalamic-pituitary-adrenal axis and suppresses peripheral immune function by a CRH-dependent mechanism. It is unknown if IL-1 can similarly act within the brain to cause peripheral immunosuppression in the primate and to what extent this could be attributed to the IL-1-induced increase in ACTH and cortisol levels. In this study we have characterized the pituitary-adrenal and peripheral lymphocyte responses to IL-1 alpha (4.2 micrograms) infused over 30 min into the lateral ventricle of ovariectomized monkeys (n = 5) as compared with responses to an intravenous (i.v.) ACTH infusion (1 microgram/h for 7 h; n = 4). Four serial blood samples were obtained for ACTH and cortisol determination and for lymphocyte isolation during a 1-hour baseline and for 7 h after IL-1 or ACTH. Lymphocyte proliferation was measured by 3H-thymidine uptake in response to stimulation with phytohemagglutinin. In all 5 animals, IL-1 alpha caused rapid and profound suppression of lymphocyte mitogen responsiveness for 7 h. Baseline lymphocyte proliferation was 51,800 +/- 9,780 cpm and suppressed to a nadir of 4.5% with a mean of 23% baseline over 7 h (p < 0.001). Mean ACTH and cortisol levels increased from 33 +/- (SEM) 4.6 pg/ml and 43 +/- 4.0 micrograms/dl, respectively, during the control period to 90 +/- 14 pg/ml and 56 +/- 2.6 micrograms/dl, respectively, after IL-1 (p < 0.01). Before i.v. ACTH, baseline lymphocyte proliferation was 49,400 +/- 2,820 cpm, and suppressed to a mean of 64% of baseline during ACTH infusion (p < 0.05). Mean ACTH and cortisol levels increased from 48 +/- 5.0 pg/ml and 43 +/- 2.0 micrograms/dl, respectively, to 170 +/- 34 pg/ml and 66 +/- 2.3 micrograms/dl, respectively, during the ACTH infusion (p < 0.01). Lymphocyte suppression after i.c.v. IL-1 was much more profound than after i.v. ACTH (p < 0.01); the area under the IL-1 response curve was 37% of the area under the ACTH response curve. These studies demonstrate for the first time in the primate that centrally injected IL-1 has a profound suppressive effect on lymphocyte function. They also show for the first time in any species that there appears to be a significant immunosuppressive message produced by i.c.v. IL-1 that is not accounted for by the associated increases in ACTH and cortisol.