Activation of melanocortin 4 receptors reduces the inflammatory response and prevents apoptosis induced by lipopolysaccharide and interferon-gamma in astrocytes

CARUSO, C.; DURAND, D.; SCHIÖT, H.B.; REY, R.; SEILICOVICH, A.; LASAGA, M.

ENDOCRINOLOGY

Año: 2007 vol. 148 p. 4918 - 4926

0013-7227

á-melanocyte stimulating hormone (á-MSH) exerts an immunomodulatory action in the brain and may play a neuroprotective role acting through melanocortin 4 receptors (MC4Rs). In the present study, we show that MC4Rs are constitutively expressed in astrocytes as determined by immunocytochemistry, RT-PCR, and Western Blot analysis. á-MSH (5 ìM) reduced bacterial lipopolysaccharide (LPS, 1 ìg/ml) + Interferon-ã (IFN-ã, 50 ng/ml) induced nitric oxide production and the expression of inducible nitric oxide synthase (iNOS) in cultured astrocytes after 24 h. á-MSH also attenuated the stimulatory effect of LPS/IFN-ã on prostaglandin E2 release and cyclooxygenase-2 (COX-2) expression. Treatment with HS024, a selective MC4R antagonist, blocked the anti-inflammatory effects of á-MSH, suggesting a MC4R mediated mechanism in the action of this melanocortin. In astrocytes, LPS/IFN-ã treatment reduced cell viability, increased the number of TUNELpositive cells and activated caspase-3. á-MSH prevented these apoptotic events and this cytoprotective effect was abolished by HS024. LPS/IFN-ã decreased Bcl-2 whereas it increased Bax protein expression in astrocytes, thus increasing the Bax/Bcl-2 ratio. á-MSH produced a shift in Bax/Bcl-2 ratio towards astrocyte survival since it increased per se Bcl-2 expression and also prevented the effect of LPS/IFN-ã on Bax and Bcl-2 expression. In summary, these findings suggest that á-MSH, through MC4R activation, attenuates LPS/IFN- ã-induced inflammation by decreasing iNOS and COX-2 expression and prevents LPS/IFN-ã- induced apoptosis of astrocytes by modulating the expression of proteins of the Bcl-2 family