In vitro suppression of inflammatory cytokine response by methionine sulfoximine

Abstract

BackgroundThe glutamine synthetase inhibitor methionine sulfoximine (MSO), shown previously to prevent death caused by an inflammatory liver response in mice, was tested on in vitro production of cytokines by mouse peritoneal macrophages triggered with lipopolysaccharide (LPS).ResultsMSO significantly reduced the production of Interleukin 6 (IL-6) and Tumor Necrosis Factor Alpha (TNFα) at 4 and 6 h after LPS-treatment. This reduction did not result from decreased transcription of IL-6 and TNFα genes, and therefore appeared to result from post-transcriptional inhibition of synthesis of these cytokines. MSO treatment did not inhibit total protein synthesis and did not reduce the production of a third LPS-triggered cytokine CXCL1, so the effect was not a toxic or global downregulation of the LPS response. The anti-inflammatory effects of a glutamine synthetase inhibitor were seen even though the medium contained abundant (2 mM) glutamine, suggesting that the target for this activity was not glutamine synthetase. In agreement with this hypothesis, the L,R isomer of MSO, which does not inhibit glutamine synthetase and was previously thought to be inert, both significantly reduced IL-6 secretion in isolated macrophages and increased survival in a mouse model for inflammatory liver failure.ConclusionsOur findings provide evidence for a novel target of MSO. Future attempts to identify the additional target would therefore also provide a target for therapies to treat diseases involving damaging cytokine responses.

Pyrogenic and Precipitated Amorphous Silica Nanoparticles Differentially Affect Cell Responses to LPS in Human Macrophages

“…While a low GS expression would be associated with the M1 phenotype, its up-regulation has been considered a typical M2 feature [ 50 ]. Recent studies, performed on several models of innate immunity cells, supported this hypothesis, indicating that GS inhibition has a clear-cut pro-inflammatory effect [ 50 , 51 , 52 , 53 ]. If this were indeed the case, the increase in GS expression promoted by LPS would possibly constitute a kind of negative feedback to avoid an excessive stimulation of inflammatory cells.…”

Agent Clustering Strategy Based on Metabolic Flux Distribution and Transcriptome Expression for Novel Drug Development

“…Some studies have indicated that Rifampicin has anti-inflammatory effects [51,52]. In addition to the approved agents, experimental agent L-methionine sulfoximine was also clustered into group 7 with its pharmacodynamics unknown, and it has been reported to be a novel anti-inflammatory agent [53,54]. These results suggest that the drugs with a similar pharmacology from the same group may provide a reference of new drug development through this grouping approach.…”

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“…GS inhibition has been shown to protect astrocytes from hyperammonemia for 24 h (Tanigami et al 2005). However, the in vitro medium used in this study contained abundant glutamine, suggesting that the protective effect of MSO may have resulted from its isomer rather than the inhibition of GS (Peters et al 2018). The concentrations of glutamate and glutamine must be maintained to prevent excitotoxity, and a high dose of MSO has been shown to irreversibly inhibit GS activity (Phelps 1975).…”

“…Although MSO remarkably activates interleukin 6 and tumor necrosis factor alpha under conditions of lipopolysaccharide treatment (Peters et al 2018), MSO is not a potent drug to prevent neuron death due to its effects on the accumulation of glycogen, which in turn can trigger convulsions. The anti-inflammatory effect of MSO might be relevant to two functional domains of RSK1, the N terminal kinase domain (part of the protein kinase A) and the C terminal kinase domain (part of calmodulin-dependent protein kinase [CaMK]), which are heavily involved in the activation of its downstream proteins, such as CREB and Bcl2 (Lin et al 2019).…”