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promoter activity by S-adenosylmethionine and 5'-methylthioadenosine
1 USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA; Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
2 Norris Comprehensive Cancer Center, Department of Urology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
3 Parque Tecnologico, CIC Biogune, Bizkaia, Spain
4 USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA; USC Research Center for Liver Diseases, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA; Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
5 USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA; USC Research Center for Liver Diseases, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA; Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
* To whom correspondence should be addressed. E-mail: htsukamo{at}usc.edu.
S-adenosylmethionine (SAM) is the principal biological methyl donor and precursor for
polyamines. SAM is known to be hepatoprotective in many liver disease models in which
TNF
is implicated. The present study investigated whether and how SAM inhibited LPS-stimulated
TNF expression in Kupffer cells (hepatic macrophages). SAM downregulated
TNF expression in LPS-stimulated Kupffer cells at the transcriptional level as suggested by
a transfection experiment with a TNF promoter-reporter gene. This inhibition was not
meatiated through decreased NF-
B binding to four putative B binding elements located
within the promoter. The inhibited promoter activity was neither prevented by over
expression of p65 or/and its co-activator p300, nor enhanced by over expression of CARM-1,
an enzyme that methylates p300 and inhibits a p65-p300 interaction. SAM did not lead to
DNA methylation at the most common CpG target sites in the TNF promoter. Moreover, 5'-
methylthioadenosine (MTA) that is derived from SAM but does not serve as a methyl donor,
recapitulated SAM's effect with more potency. These data demonstrate that SAM inhibits
TNF expression at the level down stream of NF-B binding and at the level of the promoter
activity via mechanisms that do not appear to involve the limited availability of p65 or p300.
Further, our study is the first to demonstrate a potent inhibitory effect on NF-B promoter
activity and TNF expression by a SAM's metabolite, MTA.
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