Stimulation of tumor necrosis factor alpha production in human monocytes by inhibitors of protein phosphatase 1 and 2A.

Sung, S.-S. J.; Walters, Jay A.; Fu, Shu Man

doi:10.1084/jem.176.3.897

Cited by 43 publications

(21 citation statements)

References 16 publications

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“…Kupffer cells might be especially sensitive to the inhibitory or oxidative stress-mediated effects of OA because we showed that OA concentration in excess of 50 µM, which did not stress other cell types [28], did lead to induction of TNF-␣ mRNA. OA-mediated induction of TNF-␣ mRNA is consistent with previous observations in macrophage systems [29,30]. TNF-␣ mRNA was induced by LPS in the presence of NAC in cells treated with low concentrations of OA that by themselves were innocuous.…”

Section: Discussionsupporting

confidence: 80%

“…If NAC were operating exclusively as a passive antioxidant then one would expect that it would have inhibited the oxidative stress aspects of OA. These results, together with previous studies in other macrophage populations [29,30], may suggest the presence of an alternative signaling pathway that potentially mediates the inactivation of the inflammatory response.…”

Section: Fig 3 Nac Inhibits Nuclear Nf-b Activity (A) While It Doesmentioning

confidence: 48%

“…Other studies in human monocytes and murine macrophages have shown that OA induces TNF-␣ mRNA and leads to a prolonged half-life for LPS-mediated TNF-␣ mRNA [29,30]. Thus we wondered if there was a causal relationship between the OA effect on the half-life of LPSmediated TNF-␣ mRNA and its ability to induce oxidative stress.…”

Section: Fig 3 Nac Inhibits Nuclear Nf-b Activity (A) While It Doesmentioning

confidence: 98%

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Inhibition of LPS-mediated activation in rat Kupffer cells by N-acetylcysteine occurs subsequent to NF-κB translocation and requires protein synthesis

Fox

Leingang

1998

Journal of Leukocyte Biology

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Activation of the resident hepatic macrophage population, Kupffer cells, leads to production of mediators that initiate, potentiate, and modulate hepatic injury. Recent studies have shown that activation of the pluripotent transcription factor nuclear factor-B (NF-B) is an important step in the induction of inflammatory cytokines, chemokines, growth factors, cell adhesion proteins, and cytokine receptors, thus efforts have been focused to modulate its activity. A common observation in diverse experimental systems is that oxidant stress activates NF-B and antioxidant drugs prevent activation and subsequent inflammatory gene transcription. However, we have recently shown that the inhibitory effect of N-acetylcysteine (NAC) is independent of its role as a substrate of glutathione synthesis and NAC can inhibit Kupffer cell activation at points beyond the initiation of activation. The goal of this study was to characterize the mechanism for NAC-mediated inhibition of Kupffer cell activation. We show for the first time that this process requires a cellular synthetic response to prevent both NF-B and tumor necrosis factor ␣ (TNF-␣) mRNA activation. Furthermore, NACmediated inhibition occurs after degradation of IB-␣ and nuclear translocation of NF-B. These data suggest that inhibition of Kupffer cell activation by NAC is a nuclear event and offers a potential approach to modulate Kupffer cell activation during hepatic injury.

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Section: Discussionsupporting

confidence: 80%

Section: Fig 3 Nac Inhibits Nuclear Nf-b Activity (A) While It Doesmentioning

confidence: 48%

Section: Fig 3 Nac Inhibits Nuclear Nf-b Activity (A) While It Doesmentioning

confidence: 98%

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Inhibition of LPS-mediated activation in rat Kupffer cells by N-acetylcysteine occurs subsequent to NF-κB translocation and requires protein synthesis

Fox

Leingang

1998

Journal of Leukocyte Biology

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“…The specificity of the TNF-␣ response in cardiac cells was assessed by examining the action of agents known to induce TNF-␣ expression in myeloid cells (9,29). As shown in Fig.…”

Section: Effect Of Nf-b Inhibitors and Activators On Tnf-␣ Secretion mentioning

confidence: 99%

Endotoxin stress-response in cardiomyocytes: NF-κB activation and tumor necrosis factor-α expression

Wright¹,

Singh

Hasday

et al. 2002

American Journal of Physiology-Heart and Circulatory Physiology

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Although tumor necrosis factor (TNF)-α is implicated in numerous cardiac pathologies, the intracellular events leading to its production by heart cells are largely unknown. The goal of the present study was to identify the role of the transcription factor nuclear factor (NF)-κB in this process. Among the many inducers of TNF-α expression in myeloid cells, only lipopolysaccharide (LPS) led to its induction in cultured neonatal myocytes. LPS also activated the NF-κB pathway, as evidenced by the degradation of the inhibitory protein IκB and the appearance of NF-κB-binding complexes in nuclear extracts. Furthermore, inhibitors of NF-κB activation, such as lactacystin, MG132, and pyrrolidine dithiocarbamate, were found to completely block the production of TNF-α in response to LPS stimulation, indicating a requirement of NF-κB for TNF-α expression. However, interleukin-1β and phorbol 12-myristate 13-acetate also activated NF-κB but did not evoke TNF-α expression, revealing that this factor is not sufficient for cytokine production. Detailed examination of the NF-κB cascade revealed that cardiac cells displayed a unique pattern of IκB degradation in response to LPS, with IκBβ but not IκBα being degraded upon stimulation. Additionally, two specific p65-containing DNA-binding complexes were observed in the nuclear extracts of neonatal cardiomyocytes: an inducible complex that is necessary for TNF-α expression and a constitutive species. Taken together, these results reveal that NF-κB is not only involved in cytokine production but also may be linked to other pathways that subserve a constitutive, protective mechanism for the heart cell.

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“…Protein kinases and phosphatases regulate TNF-␣ gene activity. TNF-␣ gene expression is blocked by tyrosine kinase inhibitors (48) and stimulated by inhibitors of phosphatases 1 and 2A (51). Considering the ability of 2-AP to inhibit splicing of TNF-␣ mRNA from precursor transcripts, we examined the effects of H7 and STS, inhibitors of protein kinases C and A, on PMA-induced TNF-␣ RNA expression ( Fig.…”

Section: -Ap Elicits Accumulation Of Unstable Functional Tnf-␣ Precmentioning

confidence: 99%

2-Aminopurine Selectively Inhibits Splicing of Tumor Necrosis Factor Alpha mRNA

Jarrous

Osman

Kaempfer

1996

Molecular and Cellular Biology

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2-Aminopurine (2-AP) inhibits specific kinases that phosphorylate the ␣ subunit of eukaryotic translation initiation factor 2. One of these, PKR, is also involved in signal transduction. We show here that 2-AP selectively inhibits expression of tumor necrosis factor alpha (TNF-␣) mRNA in primary human lymphoid cells. 2-AP does not inhibit transcription of the human TNF-␣ gene, nor does it affect mRNA stability. Instead, the flow of short-lived precursor transcripts into mature TNF-␣ mRNA is blocked. When 2-AP is present during induction, unspliced TNF-␣ precursor transcripts accumulate at the expense of mRNA. Using RNase protection analysis with genomic probes for different exon-intron junctions, we show that 2-AP blocks splicing of TNF-␣ mRNA. Neither the TNF-␤ nor the interleukin-1␤ gene shows such regulation. 2-AP also inhibits splicing of precursor RNA transcribed from an exogenous human TNF-␣ gene. Sequences within this gene thus confer sensitivity to 2-AP. Yet, control is not exerted at a specific splice site. Our results reveal the involvement of a 2-AP-sensitive component, expressed in functional form before induction, in the splicing of TNF-␣ mRNA.

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Stimulation of tumor necrosis factor alpha production in human monocytes by inhibitors of protein phosphatase 1 and 2A.

Cited by 43 publications

References 16 publications

Inhibition of LPS-mediated activation in rat Kupffer cells by N-acetylcysteine occurs subsequent to NF-κB translocation and requires protein synthesis

Inhibition of LPS-mediated activation in rat Kupffer cells by N-acetylcysteine occurs subsequent to NF-κB translocation and requires protein synthesis

Endotoxin stress-response in cardiomyocytes: NF-κB activation and tumor necrosis factor-α expression

2-Aminopurine Selectively Inhibits Splicing of Tumor Necrosis Factor Alpha mRNA

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