SAMe prevents the up regulation of toll-like receptor signaling in Mallory-Denk body forming hepatocytes.
Exp Mol Pathol
; 88(3): 376-9, 2010 Jun.
Article
in En
| MEDLINE
| ID: mdl-20206621
ABSTRACT
Mallory-Denk body (MDB) formation is a component of alcoholic and non alcoholic hepatitis. In the present study, the role of the toll-like receptor (TLR) signaling pathway was investigated in the mechanism of MDB formation in the DDC-fed mouse model. Microarray analysis data mining, performed on the livers of drug-primed mice refed DDC, showed that TLR2/4 gene expression was significantly up regulated by DDC refeeding. SAMe supplementation prevented this up regulation and prevented the formation of MDBs. qRT-PCR analysis confirmed these results. TLR2/4 activates the adapter protein MyD88. The levels of MyD88 were increased by DDC refeeding. The increase of MyD88 was also prevented by SAMe supplementation. Results showed that MyD88-independent TLR3/4-TRIF-IRF3 pathway was not up regulated in the liver of DDC refed mice. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is the downstream protein recruited by the MyD88/IRAK protein complex, and is involved in the regulation of innate immune responses. Results showed a significant increase in the levels of TRAF-6. TRAF-6 activation leads to activation of NFkB and the mitogen-activated protein kinase (MAPK) cascade. The TRAF-6 increase was ameliorated by SAMe supplementation. These results suggest that DDC induces MDB formation through the TLR2/4 and MyD88-dependent signaling pathway. In conclusion, SAMe blocked the over-expression of TLR2/4, and their downstream signaling components MyD88 and TRAF-6. SAMe prevented the DDC-induced up regulation of the TLR signaling pathways, probably by preventing the up regulation of INF-gamma receptors by DDC feeding. INFgamma stimulates the up regulation of TLR2. The ability of SAMe feeding to prevent TLR signaling up regulation has not been previously described.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
S-Adenosylmethionine
/
Hepatocytes
/
Toll-Like Receptors
Type of study:
Etiology_studies
/
Prognostic_studies
Limits:
Animals
/
Humans
/
Male
Language:
En
Journal:
Exp Mol Pathol
Year:
2010
Document type:
Article
Affiliation country:
United States