Cytokine mRNA decay is accelerated by an inhibitor of p38-mitogen-activated protein kinase

Wang, S.-W.; Pawlowski, John E.; Wathen, Scott T.; Kinney, S. D.; Lichenstein, Henri S.; Manthey, Carl L.

doi:10.1007/s000110050499

Cited by 101 publications

(72 citation statements)

References 17 publications

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“…Indeed, we observed that the expression of TNF-␣ and members of the IL-1 family was partially reduced by SB203580 treatment. It remains to be determined whether these inhibitory effects are transcriptional or posttranscriptional, because recent experiments demonstrate that inhibition of p38 MAPK can lead to specific mRNA destabilization (47,48). One possible explanation is that p38 MAPK inhibition interfered with the normal process of DC maturation by affecting proinflammatory cytokine expression through NF-B negative modulation.…”

Section: Discussionmentioning

confidence: 99%

A Critical Role for p38 Mitogen-Activated Protein Kinase in the Maturation of Human Blood-Derived Dendritic Cells Induced by Lipopolysaccharide, TNF-α, and Contact Sensitizers

Arrighi

Rebsamen

Rousset

et al. 2001

The Journal of Immunology

383

325

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We investigated the involvement of mitogen-activated protein kinases (MAPKs) in the maturation of CD83− dendritic cells (DC) derived from human blood monocytes. Maturating agents such as LPS and TNF-α induced the phosphorylation of members of the three families of MAPK (extracellular signal-regulated kinase l/2, p46/54 c-Jun N-terminal kinase, and p38 MAPK). SB203580, an inhibitor of the p38 MAPK, but not the extracellular signal-regulated kinase l/2 pathway blocker PD98059, inhibited the up-regulation of CD1a, CD40, CD80, CD86, HLA-DR, and the DC maturation marker CD83 induced by LPS and TNF-α. In addition, SB203580 inhibited the enhancement of the allostimulatory capacity and partially prevented the down-regulation of FITC-dextran uptake induced by LPS and TNF-α. Likewise, SB203580 partially prevented the up-regulation of IL-1α, IL-1β, IL-lRa, and TNF-α mRNA upon stimulation with LPS and TNF-α, as well as the release of bioactive TNF-α induced by LPS. DC maturation induced by the contact sensitizers 2,4-dinitrofluorobenzene and NiSO4, as seen by the up-regulation of CD80, CD86, and CD83, was also coupled to the phosphorylation of p38 MAPK, and was inhibited by SB203580. The irritants SDS and benzalkonium chloride that do not induce DC maturation did not trigger p38 MAPK phosphorylation. Together, these data indicate that phosphorylation of p38 MAPK is critical for the maturation of immature DC. These results also suggest that p38 MAPK phosphorylation in DC may become useful for the identification of potential skin contact sensitizers.

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Section: Discussionmentioning

confidence: 99%

A Critical Role for p38 Mitogen-Activated Protein Kinase in the Maturation of Human Blood-Derived Dendritic Cells Induced by Lipopolysaccharide, TNF-α, and Contact Sensitizers

Arrighi

Rebsamen

Rousset

et al. 2001

The Journal of Immunology

383

325

View full text Add to dashboard Cite

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“…TNF␣ expression is activated mainly by the transcription factor NF-B and by the MAP kinase (MAPK) pathways (the ERK, JNK, and p38 MAPK pathways). Recent studies have shown that the p38 MAPK pathway in particular plays an important role in posttranscriptional regulation that leads to mRNA stabilization (41). The p38 MAPK pathway also strongly induces and activates TTP, which down-regulates TNF␣ (42)(43)(44)(45).…”

Section: Discussionmentioning

confidence: 99%

Butyrate suppresses tumor necrosis factor α production by regulating specific messenger RNA degradation mediated through acis-acting AU-rich element

Fukae¹,

Amasaki²,

Yamashita³

et al. 2005

Arthritis Rheum

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Objective. To study the capacity of butyrate to inhibit production of tumor necrosis factor ␣ (TNF␣) in macrophage-like synoviocytes (MLS) from patients with rheumatoid arthritis (RA), in human peripheral monocytes, and in murine RAW264.7 macrophages.Methods. The concentrations of TNF␣ in culture supernatants of these cells were measured using enzyme-linked immunosorbent assay. The expression levels of various messenger RNAs (mRNA), such as those for TNF␣, the mRNA-binding protein TIS11B, and luciferase, were measured using real-time quantitative polymerase chain reaction. The in vitro effects of butyrate on transcriptional regulation were evaluated by transfection with various reporter plasmids in RAW264.7 macrophages. The effects of TIS11B on TNF␣ expression were examined using an overexpression model of TIS11B in RAW264.7 cells.Results. Butyrate suppressed TNF␣ protein and mRNA production in MLS and monocytes, but paradoxically enhanced transactivation of the TNF␣ promoter. Expression of the AU-rich element (ARE)-binding protein TIS11B was up-regulated by butyrate. Induction of TNF␣ mRNA by lipopolysaccharide was significantly inhibited when TIS11B was overexpressed. Butyrate facilitated the degradation of luciferase transcripts containing the 3-untranslated region (3-UTR) of TNF␣, and this effect was dependent on the ARE in the 3-UTR that is known to be involved in the regulation of mRNA degradation.Conclusion. These results indicate that butyrate suppresses TNF␣ expression by facilitating mRNA degradation mediated through a cis-acting ARE. Butyrate has the ability to regulate TNF␣ at the mRNA level and is therefore a potential therapeutic drug for RA patients.

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“…Because the 3Ј UTR of IL-2 contains AREs, and IL-2 mRNA stability is the same in both C57BL/6 and DBA/2 splenocytes, altered Th2 cytokine mRNA stability between these two strains may involve modulation by some additional mechanism, perhaps differential expression of Th1-or Th2-specific trans-acting factors. In addition to AREs, the activities of p38 MAP kinase and tristetrapolin have been shown to modulate the half-lives of short-lived transcripts (42)(43)(44)(45). It is possible that p38 and tristetrapolin could modulate mRNA stability and that differential expression or activation of these molecules might account for altered Th2 cytokine mRNA stability in DBA/2 and C57BL/6 splenocytes.…”

Section: Discussionmentioning

confidence: 99%

Altered IL-4 mRNA Stability Correlates with Th1 and Th2 Bias and Susceptibility to Hypersensitivity Pneumonitis in Two Inbred Strains of Mice

Butler

Monick

Yarovinsky

et al. 2002

The Journal of Immunology

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Previously, we have shown in a model of hypersensitivity pneumonitis that Th1-biased C57BL/6 mice are susceptible and Th2-biased DBA/2 mice are resistant to disease. We also showed that this was explained in part by differential regulation of IL-12 by IL-4. For these reasons, we postulated that C57BL/6 and DBA/2 mice differentially express IL-4. In this study, we show that C57BL/6 immune cells express Th2 but not Th1 cytokines at lower levels than DBA/2 cells. We also found that C57BL/6 splenocytes exhibit decreased mRNA stability of Th2 cytokines, relative to DBA/2 splenocytes. Stability of IL-2 and IFN-γ were similar in the two strains of mice. Differences in Th2 cytokine mRNA stability between C57BL/6 and DBA/2 cells were not due to sequence polymorphism at specific regions of the IL-4/IL-13 locus. Furthermore, expression of Th1- and Th2-specific transcription factors T-bet and GATA-3, as well as the nuclear factor of activated T cells transcription factor, NFATc, was not significantly different between the two mice. Our data suggest that decreased mRNA stability of Th2 cytokines in C57BL/6 splenocytes may underlie the differential susceptibility to hypersensitivity pneumonitis between C57BL/6 and DBA/2 mice. Moreover, our results indicate that regulation of mRNA stability may serve as an important mechanism underlying Th1/Th2 immune polarization.

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Cytokine mRNA decay is accelerated by an inhibitor of p38-mitogen-activated protein kinase

Abstract: Specific mRNA destabilization represents an important and novel site of action for the cytokine suppressive effects of p38 inhibitors.

Cited by 101 publications

References 17 publications

A Critical Role for p38 Mitogen-Activated Protein Kinase in the Maturation of Human Blood-Derived Dendritic Cells Induced by Lipopolysaccharide, TNF-α, and Contact Sensitizers

A Critical Role for p38 Mitogen-Activated Protein Kinase in the Maturation of Human Blood-Derived Dendritic Cells Induced by Lipopolysaccharide, TNF-α, and Contact Sensitizers

Butyrate suppresses tumor necrosis factor α production by regulating specific messenger RNA degradation mediated through acis-acting AU-rich element

Altered IL-4 mRNA Stability Correlates with Th1 and Th2 Bias and Susceptibility to Hypersensitivity Pneumonitis in Two Inbred Strains of Mice

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