We previously showed that S-adenosylmethionine (SAMe) and its metabolite 
methylthioadenosine (MTA) blocked lipopolysaccharide (LPS)-induced tumor 
necrosis factor alpha (TNFalpha) expression in RAW (murine macrophage cell line) 
and Kupffer cells at the transcriptional level without affecting nuclear factor 
kappa B nuclear binding. However, the exact molecular mechanism or mechanisms of 
the inhibitory effect were unclear. While SAMe is a methyl donor, MTA is an 
inhibitor of methylation. SAMe can convert to MTA spontaneously, so the effect 
of exogenous SAMe may be mediated by MTA. The aim of our current work is to 
examine whether the mechanism of SAMe and MTA's inhibitory effect on 
proinflammatory mediators might involve modulation of histone methylation. In 
RAW cells, we found that LPS induced TNFalpha expression by both transcriptional 
and posttranscriptional mechanisms. SAMe and MTA treatment inhibited the 
LPS-induced increase in gene transcription. Using the chromatin 
immunoprecipitation assay, we found that LPS increased the binding of 
trimethylated histone 3 lysine 4 (H3K4) to the TNFalpha promoter, and this was 
completely blocked by either SAMe or MTA pretreatment. Similar effects were 
observed with LPS-mediated induction of inducible nitric oxide synthase (iNOS). 
LPS increased the binding of histone methyltransferases Set1 and 
myeloid/lymphoid leukemia to these promoters, which was unaffected by SAMe or 
MTA. The effects of MTA in RAW cells were confirmed in vivo in LPS-treated mice. 
Exogenous SAMe is unstable and converts spontaneously to MTA, which is stable 
and cell-permeant. Treatment with SAMe doubled intracellular MTA and 
S-adenosylhomocysteine (SAH) levels. SAH also inhibited H3K4 binding to TNFalpha 
and iNOS promoters.
CONCLUSION: The mechanism of SAMe's pharmacologic inhibitory effect on 
proinflammatory mediators is mainly mediated by MTA and SAH at the level of 
histone methylation.