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INFLAMMATION/IMMUNITY/MEDIATORS

Inhibition of lipopolysaccharide-stimulated TNF- promoter activity by S-adenosylmethionine and 5'-methylthioadenosine

¹Research Center for Alcoholic Liver and Pancreatic Diseases, University of Southern California-University of California, Los Angeles 90033; ²Research Center for Liver Diseases, University of Southern California, Los Angeles 90033; ³Department of Pathology and ⁴Norris Comprehensive Cancer Center, Los Angeles; Department of Urology, Division of ⁵Gastrointestinal and Liver Diseases and Department of Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033; ⁶CIC Biogune, Parque Tecnológico, Bizkaia, Spain; ⁷Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California 90073

Submitted 24 July 2003 ; accepted in final form 19 March 2004

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 mediated through decreased NF-B binding to four putative B binding elements located within the promoter. The inhibited promoter activity was neither prevented by overexpression of p65 and/or its coactivator p300 nor enhanced by overexpression of coactivator-associated arginine methyltransferase-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), which 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 downstream 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. Furthermore, 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.

Kupffer cells; macrophages; gene regulation; nuclear factor-B

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