alpha-MSH MODULATES TNF-alpha AND IL-1beta EXPRESSION IN CULTURED ASTROCYTES AND NEURONS

CARUSO CARLA; PÉREZ MARÍA DE LA CRUZ; DURAND DANIELA; SÁNCHEZ MÓNICA; SCIMONELLI TERESA; LASAGA MERCEDES

Toronto, Canadá

Congreso; The Endocrine Society`s 89th Annual Meeting; 2007

The Endocrine Society

Inflammatory mediators such as cytokines (e.g. TNF-alpha and IL1-alpha ) and nitric oxide (NO) are increased in neurodegenerative diseases suggesting that these factors can contribute to neural damage. alpha-melanocyte stimulating hormone (alpha -MSH) is a melanocortin that has systemic and central anti-inflammatory properties. We previously demonstrated that alpha-MSH can reduced hypothalamic NO and prostaglandins production induced by lipopolysaccharide (LPS) through melanocortin receptor 4 (MC4R) (1). Since astrocytes and neurons have different responses to pro-inflammatory stimuli and express melanocortin receptors, we investigated the effect of LPS (1 ug/ml) + IFN- gamma (50 ng/ml) and alpha -MSH (5 uM) on the gene expression of TNF- alpha and its receptors (TNFR1 and TNFR2) in cultured rat astrocytes and hypothalamic neurons (determined by RT-PCR). In astrocytes, mRNA levels of TNF- and TNFR2 were increased by LPS+IFN- treatment whereas TNFR1 levels were not modified after 24 h. alpha-MSH per se did not modify TNF-alpha , TNFR1 or TNFR2 expression. However, this melanocortin significantly attenuated the increase in the expression of TNF-alpha induced by LPS+IFN-gamma by 40% (p0.05) whereas it had no effect on TNFR2 gene expression. This anti-inflammatory effect was not observed in the presence of a selective MC4R antagonist (HS024, 0.5 uM). In hypothalamic neurons, mRNA levels of TNF-alpha , TNFR1 and TNFR2 were increased by LPS+IFN- treatment after 24 h. Again, alpha-MSH reduced TNF- expression induced by LPS+IFN- gamma in these cells by 45% (p0.05) whereas per se had no effect. We also investigated the expression of IL-1 and IL-1 receptor 1 (IL-1R1) in astrocytes. IL-1 and IL-1R1 mRNA levels were significantly increased by LPS+ IFN-gamma treatment by 4 fold and 2 fold respectively. alpha-MSH attenuated IL-1 and IL-1R1 expression induced by LPS+IFN- gamma by 20 % and 43% respectively (p0.05) . Treatment with the selective MC4R antagonist prevented the inhibitory effect of the neuropeptide. These data suggest that alpha-MSH has an anti-inflammatory effect by attenuating TNF-alpha expression induced by LPS+INF-gamma in hypothalamic neurons and astrocytes in culture. Moreover, this melanocortin also decreased the stimulatory effect of LPS+INF-gamma on IL-1 and IL-1R1 gene expression in astrocytes. The anti-inflamatory action of alpha-MSH may be exerted via MC4 receptors. References: (1) Caruso C et al., Neuroendocrinology 2004 79:278