Detection of Melanocortin 4 Receptor in rat liver and its regulation during acute phase response

As member of the defense system, liver is inextricably linked with the acute phase response (APR). On the other hand, liver cells may be the target of noxious material released from injured tissue or injuring agents.The melanocortin 4 receptor (MC4R) is known for the mediation of anti-inflammatory signals which controls the production of several pro-inflammatory cytokines. Acute phase reaction was induced in rats by intramuscular injection of turpentine oil (TO). Animals were sacrificed at different time points after injection, blood and liver tissue were taken and frozen immediately. Liver tissue was used for immunostaining of cryostat sections, protein extraction and for RNA extraction. Western blotting and RT-PCR was performed for protein and RNA analysis respectively. Furthermore isolated hepatocytes and Kupffer cells were treated in vitro with endotoxin in the presence or absence of MC4R-agonists or antagonists. Immunohistology, western blot and PCR data demonstrate the presence of the MC4R in the rat liver. We observed a significant increase of the MC4R after the induction of the APR compared to control animals both at protein and RNA level while melanocortin serum levels remains unchanged. For the first time, we reported the detection of the MC4R in the rat liver cells. Furthermore, melanocortin inhibited the presence of pro-inflammatory cytokines in Kupffer cells and chemokines gene- expression in hepatocytes in culture.In conclusion, MC4R-related cell signaling pathways in the rat liver cells could be involved in limiting the production of inflammation mediators during the APR and possibly even under physiological conditions when products of gram-negative bacteria from the intestine are transported to the liver.

acute-phase response - cytokines - inflammation - liver - melanocortin