Alpha-Melanocyte-Stimulating Hormone Abolishes IL-1- and IL-6-lnduced Corticotropin-Releasing Factor Release from the Hypothalamus in vitro

Abstract

Alpha-melanocyte-stimulating hormone (α-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 α-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^–13M), IL-1 (10^–16–10^–10 M) and/or ACTH_1–24 (10^–15–10^–9M) or α-MSH (10–¹⁵-10–⁸M); CRF release into the incubation medium was measured by RIA. None of the ACTH_1–24 or α-MSH concentrations changed basal CRF release significantly. As we reported previously, IL-6 (10^–13M) increased CRF release; this increase was suppressed, in a dose-dependent fashion, by α-MSH at concentrations of 10^–13–10^–11M, with the maximal inhibitory effect observed at 10^–13M. ACTH_1–24 also exerted a dose-dependent inhibitory effect on IL·6-stimulated CRF release but at even lower concentrations (10^–15–10^–13M) with the maximal inhibitory effect observed with the 10–^l4M concentration. Interleukin-1 β (IL-1β) evoked a bell-shaped, concentration-dependent increase in CRF secretion with a maximal effective concentration of 10–¹⁵M, 100 times lower than that previously reported for IL·6. IL-1β-induced CRF release was suppressed with a U-shaped concentration-dependent curve by α-MSH, with the maximal inhibitory effect observed with concentrations of 10^–13 and 10^–14M α-MSH. The results show that α-MSH is a potent inhibitor of IL-1β- and IL·6-induced CRF release from the hypothalamus in vitro and that ACTH_1–24 is even more potent than α-MSH (which is ACTH_1–13) in the blockade of IL·6-induced CRF release. These findings strongly support the concept of the anticytokine action of α-MSH.

Lipopolysaccharide-Induced Leptin Synthesis and Release Are Differentially Controlled by Alpha-Melanocyte-Stimulating Hormone

“…On the other hand, a second array of anti-inflammatory factors such as the ·-melanocyte-stimulating hormone (·-MSH) [2,6] and the cytokine IL-10 [7,8] are also increased by LPS to diminish the action of an otherwise exacerbated immune response that might induce tissue injury and septic shock [2,3,6,[8][9][10][11][12]. Furthermore, ·-MSH not only blocks the release of a variety of proinflammatory cytokines such as IL-1 [2,3,12,13], IL-2 [13], IL-6 [2,3], IFN-Á [13] and TNF-· [2,3,12,13] but also inhibits their biological effects since it was previously shown that ·-MSH inhibited the stimulatory action of IL-1, IL-2 and IL-6 on corticotropin-releasing hormone release from incubated hypothalami [10,11]. Therefore, these and many other actions of ·-MSH support the concept that ·-MSH plays a major anti-inflammatory role [2,3,6,[10][11][12][13].…”

“…Furthermore, ·-MSH not only blocks the release of a variety of proinflammatory cytokines such as IL-1 [2,3,12,13], IL-2 [13], IL-6 [2,3], IFN-Á [13] and TNF-· [2,3,12,13] but also inhibits their biological effects since it was previously shown that ·-MSH inhibited the stimulatory action of IL-1, IL-2 and IL-6 on corticotropin-releasing hormone release from incubated hypothalami [10,11]. Therefore, these and many other actions of ·-MSH support the concept that ·-MSH plays a major anti-inflammatory role [2,3,6,[10][11][12][13]. It was shown that ·-MSH inhibits the transcription factor NF-ÎB [14] that stimulates the synthesis of a variety of proinflammatory cytokines such as IL-1, IL-6 and TNF-· [15].…”

lnterleukin-1 Stimulates the Central Release of Corticotropin-Releasing Hormone in the Primate

“…Previous studies in the rodent have documented effects of IL-1 on CRH in brain at multiple levels. Both IL-la and IL-ip have been reported to stimulate the release of CRH from the hypothalamus in vitro [4,5,[16][17][18], The effects of IL-1 on CRH release were blocked by inhibitors of the eicosanoid cyclooxygenase pathway but not by inhibitors of the lipooxygenase pathway [5] and appear to be independent of the histaminergic and cholinergic systems [16]. IL-1 [3 has also been shown to stimulate CRH gene expression in the paraventricular nucleus (PVN) of the hypothalamus after central or peripheral injection [3,7,19].…”

Effect of Interleukin-1β on Plasma ACTH, β-Endorphin, and Corticosterone Levels in Infant and Prepubertal Rats

“…as well as intracerebroventricular IL-1P administration in adult rats (8)(9)(10). IL-1P is believed to stimulate either directly or indirectly the secretion of hypothalamic CRH (11)(12)(13) known to predominate in the control of pituitary corticotrophs. Intrahypothalamic IL-1P infusion as well as microlesions in the rat brain demonstrated the importance of certain brain structures (organum vasculosum of lamina terminalis, preoptic area, paraventricular nucleus) in the IL-induced stimulation of the HPAA (27,28).…”