Melatonin modulates signal transduction pathways and apoptosis in experimental colitis.
Various evidences have documented that the pineal secretory product melatonin exerts an important anti-inflammatory effect in different experimental models including colitis. The aim of the present study was to evaluate whether melatonin regulates the inflammatory response of experimental colitis in rats at the level of signal transduction pathway. Colitis was induced by intracolonic instillation of dinitrobenzene sulfonic acid (DNBS). Four days after DNBS administration, a substantial increase of colon TNF-alpha production was associated with the colon damage. In DNBS-treated rats, the colon injury correlated with a significant rise of apoptosis (evaluated by TUNEL coloration) which was associated with a significant increased expression of proapoptotic Bax and decreased colon content of antiapoptotic Bcl-2. This inflammatory response was also related to activation of nuclear factor-kappaB (NF-kappaB) and phosphorylation of c-Jun as well as FAS ligand expression in the colon. Treatment with melatonin (15 mg/kg daily i.p.) was associated with a remarkable amelioration of colonic disrupted architecture as well as a significant reduction of TNF-alpha. Melatonin also reduced the NF-kappaB activation and phosphorylation of c-Jun as well as the Fas ligand expression in the colon. Furthermore, melatonin reduced the expression of Bax and prevented the loss of Bcl-2 proteins as well as the presence of apoptotic cells caused by DNBS. The results of this study show that melatonin administration exerts beneficial effects in inflammatory bowel disease by modulating signal transduction pathways.
Mazzon
Emanuela
E
Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina, Italy.
Esposito
Emanuela
E
Crisafulli
Concetta
C
Riccardi
Luisa
L
Muià
Carmelo
C
Di Bella
Paolo
P
Meli
Rosaria
R
Cuzzocrea
Salvatore
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D004139:Dinitrofluorobenzene / Q000031:analogs & derivatives / Q000494:pharmacology; D004195:Disease Models, Animal; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D008550:Melatonin / Q000627:therapeutic use*; D010768:Phosphoserine / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D016207:Cytokines; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; C045305:2,4-dinitrofluorobenzene sulfonic acid; D010768:Phosphoserine; D004139:Dinitrofluorobenzene; D048031:JNK Mitogen-Activated Protein Kinases; D008550:Melatonin