<b>3‐deazaadenosine analogues inhibit the production of tumour necrosis factor‐α in RAW264.7 cells stimulated with lipopolysaccharide</b>

Jeong, Sikyoung; Lee, J H; Kim, H S; Hong, S H; Cheong, Chong-Un; Kim, I K

doi:10.1046/j.1365-2567.1996.d01-781.x

Cited by 19 publications

(19 citation statements)

References 21 publications

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“…Interestingly, others have shown that several inhibitors of SAH hydrolase also inhibit LPS-induced TNF␣ expression. 38 These observations led us to examine the effect of SAH on LPS-induced TNF␣ and iNOS expression. Similar to SAMe and MTA, SAH pretreatment significantly inhibited the ability of LPS to increase TNF␣ and iNOS mRNA levels.…”

Section: Discussionmentioning

confidence: 99%

S-adenosylmethionine inhibits lipopolysaccharide-induced gene expression via modulation of histone methylation

et al. 2008

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We previously showed that S-adenosylmethionine (SAMe) and its metabolite methylthioadenosine (MTA) blocked lipopolysaccharide (LPS)-induced tumor necrosis factor ␣ (TNF␣) expression in RAW (murine macrophage cell line) and Kupffer cells at the transcriptional level without affecting nuclear factor 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 TNF␣ 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 TNF␣ promoter, and this was completely blocked by either SAMe or MTA pretreatment. Similar effects were observed with LPSmediated 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 TNF␣ 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. (HEPATOLOGY 2008;47:1655-1666

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Section: Discussionmentioning

confidence: 99%

S-adenosylmethionine inhibits lipopolysaccharide-induced gene expression via modulation of histone methylation

et al. 2008

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“…Most changes are immunosuppressive in nature; some may be mediated through changes in NF-kB activity (Jeong et al, 1999). Thus, several compounds reduced the production of TNF-a by endotoxin-treated macrophages and protected mice against endotoxin challenge (Parmely et al, 1993;Jeong et al, 1996). Adenosine analogs also inhibited the activation of T cells and decreased the phagocytic activity of macrophages (Sung and Silverstein, 1985;Wolos et al, 1993a,b;Lambert et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

3-Deazaneplanocin A induces massively increased interferon-α production in Ebola virus-infected mice

et al. 2002

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3-Deazaneplanocin A, an analog of adenosine, is a potent inhibitor of Ebola virus replication. A single dose early in infection prevents illness and death in Ebola virus-infected mice. The ability of this and similar compounds to block both RNA and DNA viruses has been attributed to the inhibition of a cellular enzyme, S-adenosylhomocysteine hydrolase (SAH), indirectly resulting in reduced methylation of the 5% cap of viral messenger RNA. However, we found that the protective effect of the drug resulted from massively increased production of interferon-a in Ebola-infected, but not uninfected mice. Peak interferon levels increased with the extent of disease at the time of treatment, indicating that production was boosted only in virus-infected cells. Ebola virus has been shown to suppress innate antiviral mechanisms of the type I interferon response. 3-Deazaneplanocin A appears to reverse such suppression, restricting viral dissemination. Further development should focus on identifying adenosine analogues that produce a similar effect in Ebola virus-infected primates. Published by Elsevier Science B.V.

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“…Because DZA is also able to serve as a substrate for Ado-Hcy hydrolase, the interaction between DZA and Ado-Hcy hydrolase results in the accumulation of 3-deazaadenosylhomocysteine (DZAHcy) in cultured cells [2] and the liver [3]. It is also well known that DZA exerts a wide variety of biological functions such as anti-human immunodeficiency virus (HIV) activity [4], anti-inflammatory effects [5], alterations in the expression of genes like collagen IV and ICAM-1 [6,7], the inhibition of TNF-α and IL-1β expression [8], and an inhibitory effect on nuclear NF-κB transcriptional activity [9]. In addition, DZA has been reported to induce apoptosis in human and murine leukemic cell lines such as HL-60, U937 and L1210 cells [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Induction of the Intrinsic Apoptotic Pathway by 3-Deazaadenosine Is Mediated by BAX Activation in HL-60 Cells

Lee

Kang

et al. 2010

Korean J Physiol Pharmacol

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3-Deazaadenosine (DZA), a potent inhibitor of S-adenosylhomocysteine hydrolase, was previously proposed to induce intrinsic apoptosis in human leukemic cells. In the present study, we analyzed the mechanism underlying the DZA-induced intrinsic apoptotic pathway. DZA activated typical caspase-dependent apoptosis in HL-60 cells, as demonstrated by an accumulation of hypo-diploidic cells, the processing of multiple procaspases and an inhibitory effect of z-VAD-Fmk on this cell death. During DZA-induced apoptosis, cytochrome c (cyt c) was released into the cytosol. This was neither prevented by z-VAD-Fmk and nor was it associated with the dissipation of mitochondrial membrane potential (Δ Ψ m). Prior to the release of cyt c, BAX was translocated from the cytosol to mitochondria and underwent oligomerization. Finally, the overexpression of BCL-XL protected HL-60 cells from apoptosis by blocking both the cyt c release and BAX oligomerization. Collectively, these findings suggest that DZA may activate intrinsic apoptosis by stimulating BAX activation and thereby the release of cyt c.

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3‐deazaadenosine analogues inhibit the production of tumour necrosis factor‐α in RAW264.7 cells stimulated with lipopolysaccharide

Cited by 19 publications

References 21 publications

S-adenosylmethionine inhibits lipopolysaccharide-induced gene expression via modulation of histone methylation

S-adenosylmethionine inhibits lipopolysaccharide-induced gene expression via modulation of histone methylation

3-Deazaneplanocin A induces massively increased interferon-α production in Ebola virus-infected mice

Induction of the Intrinsic Apoptotic Pathway by 3-Deazaadenosine Is Mediated by BAX Activation in HL-60 Cells

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