Translational Control of NKT Cell Cytokine Production by p38 MAPK

Nagaleekar, Viswas Konasagara; Sabio, Guadalupe; Aktan, Idil; Chant, A.D.B.; Howe, Isaac W.; Thornton, Tina M.; Benoit, Patrick; Davis, Roger J.; Rincón, Mercedes; Boyson, Jonathan E.

doi:10.4049/jimmunol.1002614

Cited by 27 publications

(33 citation statements)

References 44 publications

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“…The Mnk kinases may also play roles in the production of IFNγ by NKT cells [18]. These observations combined with our results, raise the possibility of a positive feedback regulatory loop, in which Mnk kinases both regulate Type II IFN production and positively mediate Type II IFN responses.…”

Section: Rantessupporting

confidence: 66%

“…Additionally the presence of the Mnk inhibitor also suppressed IL-1β-stimulated TNFα release [17]. Inhibition of Mnk kinases also negatively regulates post-transcriptional regulation of IFNγ and IL-4 in activated murine NK cells [18] and blocks Shiga toxin mediated release of IL-1β and IL-8 [19]. Thus Mnk kinases play important roles in the control of immune responses and elucidating the precise mechanisms of Mnk mediated post-transcriptional regulation of cytokine production will have important therapeutic implications.…”

Section: Introductionmentioning

confidence: 99%

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Mnk kinases in cytokine signaling and regulation of cytokine responses

Joshi¹,

Platanias²

2012

Biomolecular Concepts

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The kinases Mnk1 and Mnk2 are activated downstream of the p38 MAPK and MEK/ERK signaling pathways. Extensive work over the years has shown that these kinases control phosphorylation of the eukaryotic initiation factor 4E (eIF4E) and regulate engagement of other effector elements, including hnRNPA1 and PSF. Mnk kinases are ubiquitously expressed and play critical roles in signaling for various cytokine receptors, while there is emerging evidence that they have important functions as mediators of pro-inflammatory cytokine production. In this review the mechanisms of activation of MNK pathways by cytokine receptors are addressed and their roles in diverse cytokine-dependent biological processes are reviewed. The clinical-translational implications of such work and the relevance of future development of specific MNK inhibitors for the treatment of malignancies and auto-immune disorders are discussed.

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Section: Rantessupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Mnk kinases in cytokine signaling and regulation of cytokine responses

Joshi¹,

Platanias²

2012

Biomolecular Concepts

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“…The p38 MAPK pathway is a key regulator of the expression of inflammatory cytokines, including IL-6 and TNF-α, the main determinant of LPS-stimulated liver damage (24)(25)(26)(27). Circulating levels of TNF-α and IL-6 after D-gal+LPS injection did not differ between WT mice and the Mkk3 -/-or Mkk6 -/-mice (Supplemental Figure 2A).…”

Section: Mkk3 and Mkk6 Collaborate In Lps-induced Hepatitismentioning

confidence: 88%

“…p38 MAPK can promote cytokine expression at the level of transcription, after transcription (by promoting mRNA stability), and translation (27,40). Il6 mRNA expression was reduced in p38γ/δ Lyz-KO macrophages, but levels of Tnfa mRNA were comparable to those in Lyzs-cre macrophages ( Figure 6B).…”

Section: Mkk3 and Mkk6 Are Not Required For Tnf-α-induced Liver Damagementioning

confidence: 91%

Eukaryotic elongation factor 2 controls TNF-α translation in LPS-induced hepatitis

González‐Terán

Cortés²,

Manieri³

et al. 2012

J. Clin. Invest.

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Bacterial LPS (endotoxin) has been implicated in the pathogenesis of acute liver disease through its induction of the proinflammatory cytokine TNF-α. TNF-α is a key determinant of the outcome in a well-established mouse model of acute liver failure during septic shock. One possible mechanism for regulating TNF-α expression is through the control of protein elongation during translation, which would allow rapid cell adaptation to physiological changes. However, the regulation of translational elongation is poorly understood. We found that expression of p38γ/δ MAPK proteins is required for the elongation of nascent TNF-α protein in macrophages. The MKK3/6-p38γ/δ pathway mediated an inhibitory phosphorylation of eukaryotic elongation factor 2 (eEF2) kinase, which in turn promoted eEF2 activation (dephosphorylation) and subsequent TNF-α elongation. These results identify a new signaling pathway that regulates TNF-α production in LPS-induced liver damage and suggest potential cell-specific therapeutic targets for liver diseases in which TNF-α production is involved.

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“…Rapid induction of proinflammatory cytokines upon exposure to inflammatory stimuli occurs prior to an increase of their mRNAs and is highly sensitive to p38 inhibitors (8). Kinases downstream of the p38 MAPKs, Mnk1 (9) and MAPK-activated protein kinase 2 (Mk2) (10) have been implicated in posttranscriptional control upon p38 MAPK activation. Both Mnk1 (11) and Mk2 (12) may stabilize proinflammatory cytokine transcripts via phosphorylation of AU-rich element (ARE)-binding proteins that interact with AREs in cytokine mRNA 3= untranslated regions (3=UTRs).…”

mentioning

confidence: 99%

p38α Mitogen-Activated Protein Kinase Depletion and Repression of Signal Transduction to Translation Machinery by miR-124 and -128 in Neurons

Lawson

Dobrikova

Shveygert

et al. 2013

Molecular and Cellular Biology

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The p38␣ to p38␦ mitogen-activated protein kinases (MAPKs) are central regulatory nodes coordinating acute stress and inflammatory responses. Their activation leads to rapid adjustment of protein synthesis, for instance translational induction of proinflammatory cytokines. The only known direct link of p38 to translation machinery is the MAPK signal-integrating kinase Mnk. Only p38␣ and p38␤ transcripts are ubiquitously expressed. These mRNAs encode highly conserved proteins that equally phosphorylate recombinant Mnk1 in vitro. We discovered that expression of the p38␣ protein, but not the p38␤ isoform, is suppressed in the brain. This is due to p38␣ depletion by two neuron-selective microRNAs (miRNAs), miR-124 and -128. Suppression of p38␣ protein was reversed by miR-124/-128 antisense oligonucleotides in primary explant neuronal cultures. Targeted p38␣ depletion reduced Mnk1 activation, which cannot be compensated by p38␤. Our research shows that p38␣ alone controls acute stress and cytokine signaling from p38 MAPK to translation machinery. This regulatory axis is greatly diminished in neurons, which may insulate brain physiology and function from p38␣-Mnk1-mediated signaling.

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Translational Control of NKT Cell Cytokine Production by p38 MAPK

Cited by 27 publications

References 44 publications

Mnk kinases in cytokine signaling and regulation of cytokine responses

Mnk kinases in cytokine signaling and regulation of cytokine responses

Eukaryotic elongation factor 2 controls TNF-α translation in LPS-induced hepatitis

p38α Mitogen-Activated Protein Kinase Depletion and Repression of Signal Transduction to Translation Machinery by miR-124 and -128 in Neurons

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