α-Melanocyte-stimulating hormone modulates lipopolysaccharide plus interferon-γ-induced tumor necrosis factor-α expression but not tumor necrosis factor-α receptor expression in cultured hypothalamic neurons

In a previous work we showed that the melanocortin alpha-melanocyte-stimulating hormone (alpha-MSH) exerts anti-inflammatory action through melanocortin 4 receptor (MC4R) in vivo in rat hypothalamus. In this work, we examined the effect of alpha-MSH on the expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) and their receptors in primary cultured rat hypothalamic neurons. We also investigated alpha-MSH's possible mechanism/s of action. alpha-MSH (5 mu M) decreased TNF-alpha expression induced by 24 h administration of a combination of bacterial lipopolysaccharide (LPS, 1 mu g/ml) plus interferon-gamma (IFN-gamma, 50 ng/ml). Expression of TNF-alpha and IL-1 beta receptors TNFR1, TNFR2 and IL-1RI, was up-regulated by LPS + IFN-gamma whereas alpha-MSH did not modify basal or LPS + IFN-gamma-induced-TNFRs or IL-1RI expression. Both alpha-MSH and LPS + IFN-gamma treatments increased CREB activation. a-MSH did not modify NF-kappa B activation induced by LPS + IFN-gamma in hypothalamic neurons. In conclusion, our data show that alpha-MSH reduces TNF-alpha expression in hypothalamic neurons by a mechanism which could be mediated by CREB. The regulation of inflammatory processes in the hypothalamus by alpha-MSH might help to prevent neurodegeneration resulting from inflammation. (c) 2010 Elsevier B.V. All rights reserved.