ALPHA-MELANOCYTE-STIMULATING HORMONE ABOLISHES IL-1-INDUCED AND IL-6-INDUCED CORTICOTROPIN-RELEASING FACTOR RELEASE FROM THE HYPOTHALAMUS IN-VITRO

Alpha-melanocyte-stimulating hormone (alpha-MSH) and adrenocorticotropic hormone (ACTH), peptides derived from the precursor proopiomelanocortin, share amino acid homology at the aminoterminus of ACTH, occur within the pituitary and the brain and are potent antipyretic compounds in cytokine-mediated fever. Because alpha-MSH and ACTH act within the hypothalamus to block leukocytic pyrogen- or cytokine-mediated fever, we hypothesized that these compounds might also be capable of blocking the action of interleukin-1 (IL-1) and interleukin-6 (IL-6) to stimulate corticotropin-releasing factor (CRF) release from the hypothalamus. Mediobasal hypothalami (MBH) were incubated in vitro. After 60 min preincubation in Krebs-Ringer bicarbonate buffer (KRB), MBH explants were incubated for 30 min with KRB alone or KRB containing IL-6 (10(-13) M), IL-1 (10(-16)-10(-10) M) and/or ACTH1-24 (10(-15)-10(-9) M) or alpha-MSH (10(-15)-10(-8) M); CRF release into the incubation medium was measured by RIA. None of the ACTH1-24 or alpha-MSH concentrations changed basal CRF release significantly. As we reported previously, IL-6 (10(-13) M) increased CRF release; this increase was suppressed, in a dose-dependent fashion, by alpha-MSH at concentrations of 10(-13)-10(-11) M, with the maximal inhibitory effect observed at 10(-13) M. ACTH 1-24 also exerted a dose-dependent inhibitory effect on IL-6-stimulated CRF release but at even lower concentrations (10(-15)-10(-13) M) with the maximal inhibitory effect observed with the 10(-14) M concentration. Interleukin-1beta (IL-1beta) evoked a bell-shaped, concentration-dependent increase in CRF secretion with a maximal effective concentration of 10(-15) M, 100 times lower than that previously reported for IL-6. IL-1beta-induced CRF release was suppressed with a U-shaped concentration-dependent curve by alpha-MSH, with the maximal inhibitory effect observed with concentrations of 10(-13) and 10(-14) M alpha-MSH. The results show that alpha-MSH is a potent inhibitor of IL-1beta- and IL-6-induced CRF release from the hypothalamus in vitro and that ACTH1-24 is even more potent than alpha-MSH (which is ACTH1-13) in the blockade of IL-6-induced CRF release. These findings strongly support the concept of the anticytokine action of alpha-MSH.