alfa-MSH modulates TNF-alfa and IL-1beta expression in cultured astrocytes and neurons

C. CARUSO; M. C. PEREZ; D. DURAND; M. SANCHEZ; T. SCIMONELLI; M. LASAGA

Toronto

Congreso; The Endocrine Society's 89th annual meeting; 2007

The Endocrine Society

Inflammatory mediators such as cytokines (e.g. TNF-a and IL1-b) and nitric oxide (NO) are increased in neurodegenerative diseases suggesting that these factors can contribute to neural damage. a-melanocyte stimulating hormone (a-MSH) is a melanocortin that has systemic and central anti-inflammatory properties. We previously demonstrated that a-MSH can reduced hypothalamic NO and prostaglandins production induced by lipopolysaccharide (LPS) through melanocortin receptor 4 (MC4R) (Caruso et al. ). 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-g (50 ng/ml) and a-MSH (5 uM) on the gene expression of TNF-a and its receptors (TNFR1 and TNFR2) in cultured rat astrocytes and hypothalamic neurons (determined by RT-PCR). In astrocytes, mRNA levels of TNF-a and TNFR2 were increased by LPS+IFN-g treatment whereas TNFR1 levels were not modified after 24 h. a-MSH per se did not modify TNF-a, TNFR1 or TNFR2 expression. However, this melanocortin significantly attenuated the increase in the expression of TNF-a induced by LPS+IFN-g by 40% ( p< 0.05) whereas it had no effect on TNFR2 gene expression induced by LPS+IFN-g. 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-a, TNFR1 and TNFR2 were increased by LPS+IFN-g treatment after 24 h. Again, a-MSH reduced TNF-a expression induced by LPS+IFN-g in these cells by 45% ( p< 0.05) whereas per se had no effect. We also investigated the expression of IL-1b and IL-1 receptor 1 (IL-1R1) in astrocytes. IL-1b and IL-1R1 mRNA levels were significantly increased by LPS+ IFN-g treatment by 4 fold and 2 fold respectively. a-MSH attenuated IL-1b and IL-1R1 expression induced by LPS+IFN-g by 20 % and 43% respectively (p