S-Adenosylmethionine Decreases Lipopolysaccharide-Induced Phosphodiesterase 4B2 and Attenuates Tumor Necrosis Factor Expression via cAMP/Protein Kinase A Pathway

Abstract

S-Adenosylmethionine (SAM) treatment has anti-inflammatory, cytoprotective effects against endotoxin-induced organ injury. An important component of the anti-inflammatory action of SAM involves down-regulation of the lipopolysaccharide (LPS)-induced transcriptional induction of tumor necrosis factor-␣ (TNF) expression by monocytes/macrophages. We examined the effect of SAM on expression and activity of LPS-induced up-regulation of phosphodiesterase 4 (PDE4), which regulates cellular cAMP levels and TNF expression. LPS treatment of RAW 264.7, a mouse macrophage cell line, led to the induction of Pde4b2 mRNA expression with no effect on Pde4a or Pde4d. SAM pretreatment led to a significant decrease in LPS-induced up-regulation of Pde4b2 expression in both RAW 264.7 cells and primary human CD14 ϩ monocytes. Of note, the decreased Pde4b2 mRNA expression correlated with the SAM-dependent increase in the transcriptionally repressive histone H3 lysine 9 trimethylation on the Pde4b2 intronic promoter region. The SAM-mediated decrease in LPS-inducible Pde4b2 up-regulation resulted in an increase in cellular cAMP levels and activation of cAMP-dependent protein kinase A (PKA), which plays an inhibitory role in LPS-induced TNF production. In addition, SAM did not affect LPS-inducible inhibitor of nuclear factor-B degradation or nuclear factor-B (NF-B)-p65 translocation into the nucleus but rather inhibited NF-B transcriptional activity. These results demonstrate for the first time that inhibition of LPS-induced PDE4B2 up-regulation and increased cAMP-dependent PKA activation are significant mechanisms contributing to the anti-TNF effect of SAM. Moreover, these data also suggest that SAM may be used as an effective PDE4B inhibitor in the treatment of chronic inflammatory disorders in which TNF expression plays a significant pathogenic role.

cAMP-dependent protein kinase activation decreases cytokine release in bronchial epithelial cells

“…Soluble TNF-␣ release from cells requires the posttranslational cleavage of a pro-TNF-␣ form by the TNF-␣-converting enzyme (TACE; ADAM-17) (21). Evidence exists that cAMP-PKA activation blocks TNF-␣ expression (9) and that cAMP-elevating agents inhibit TACE activity in alveolar epithelial cells (25). Moreover, swine CAFO dust-stimulated TNF-␣ gene expression was inhibited by cAMP in alveolar epithelial cells (7).…”

Role of phosphodiesterase-4 in alcohol-induced organ injury.

“…Work done by our group demonstrated that histone lysine 9 trimethylation (H3K9me3) in the Pde4b2 intronic promoter region plays a major role in regulating endotoxin responsive PDE4B2 mRNA expression in macrophages [137]. Specifically, a rapid and significant decline in the PDE4B2…”

“…These data strongly support the notion that alcohol predominantly affects PDE4B expression that affects brain cAMP metabolism. Although, LPS through TLR activation is a strong driver of PDE4B expression in peripheral monocytes/macrophages, it is well-documented that very little peripheral LPS gains access to the brain due to the poor passage through the blood brain barrier [135][136][137]221]. Hence, the alcohol-induced systemic endotoxemia likely plays an indirect role in inducing brain PDE4B expression and inflammation via the triggering of systemic cytokines such as TNF.…”

“…promoter-H3K9 trimethylation occurs in response to endotoxin leading to PDE4B2 transcriptional activation and mRNA expression [137]. We have not investigated the promoter-associated epigenetic modifications contributing to the induction of PDE4s in the liver and brain in the presence of alcohol.…”

“…Further, with regard to the involvement of a distinct PDE4 subfamily member, the data from Pde4b -/-animals strongly support the pathogenic involvement of PDE4B expression in the alcohol-induced decline in hepatic cAMP levels. Moreover, the key role of the gut-derived endotoxemia in ALD [134] also emphasizes the role of PDE4B, which is known to be endotoxin responsive [135][136][137].…”