Endogenous α-MSH modulates the hypothalamic-pituitary-adrenal response to the cytokine interleukin-1β

We and others have previously shown that exogenous alpha-MSH antagonizes the stimulatory effects of the cytokine interleukin (IL)-1 on the hypothalamic-pituitary-adrenal (HPA) axis, It is currently unknown, however, if endogenous alpha-MSH plays a physiological role in regulating the HPA response to IL-l. We have therefore examined the HPA response to IL-1 beta in rats pretreated with an affinity purified alpha-MSH antiserum (AS) infused intracerebroventricularly to neutralize endogenous alpha-MSH within the brain. alpha-MSH AS or a similarly purified fraction of normal rabbit serum (NRS) was injected intracerebroventricularly at 16 h and at 1 h prior to the i.c.v. injection of IL-1 beta (2 ng or 20 ng) and blood samples were collected through an indwelling atrial catheter. After 2 ng IL-1 beta, the adrenocorticotropic hormone (ACTH) response was significantly greater in the alpha-MSH AS treated rats (n = 7) compared to the NRS treated rats (n = 7) (P < 0.01); the mean ACTH level rose to a peak of 594 +/- 208 pg/ml in the alpha-MSH AS treated rats vs 274 +/- 122 pg/ml in the NRS treated rats, The area under the ACTH response curve in the alpha-MSH AS treated animals was 181% of that in the NRS treated animals (P < 0.05), A significant effect of alpha-MSH AS on the corticosterone response to i.c.v. IL-1 beta was also noted during the first 3 h of the study (P < 0.05). The mean area under the corticosterone response curve for the first 3 h in the alpha-MSH AS treated animals was 144% of that in the NRS treated animals (P < 0.05), After 20 ng IL-1 beta, the ACTH response over time was again significantly greater in the alpha-MSH AS treated rats (n = 8) compared to the NRS treated rats (n = 9) (P < 0.02); the mean ACTH level rose to a peak of 673 +/- 190 pg/ml after alpha-MSH AS vs 490 +/- 115 pg/ml after NRS, Corticosterone levels rose to a peak of 42 +/- 3.9 mu g/dl in the alpha-MSH AS treated rats vs 37 +/- 4.6 mu g/dl in the NRS treated rats; this difference was not significant, We conclude that the IL-1 beta induced stimulation of ACTH is significantly enhanced by antagonizing the activity of alpha-MSH, These results support a physiological role for endogenous alpha-MSH in limiting the HPA response to this inflammatory cytokine.