SAMe prevents the up regulation of toll-like receptor signaling in Mallory-Denk body forming hepatocytes.
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.
Bardag-Gorce
Fawzia
F
LABioMed at Harbor-UCLA Medical Center, Torrance CA 90502, USA.
Oliva
Joan
J
Lin
Andrew
A
Li
Jun
J
French
Barbara A
BA
French
Samuel W
SW
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004095:Dihydropyridines / Q000633:toxicity; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D002479:Inclusion Bodies / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D017931:DNA Primers; D004095:Dihydropyridines; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D048029:TNF Receptor-Associated Factor 6; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; C061879:diethyl 1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate; D012436:S-Adenosylmethionine