The involvement of AU-rich element-binding proteins in p38 mitogen-activated protein kinase pathway-mediated mRNA stabilisation

Dean, Jonathan L. E.; Sully, Gareth; Clark, Andrew R.; Saklatvala, Jeremy

doi:10.1016/j.cellsig.2004.04.006

Cited by 298 publications

(297 citation statements)

References 89 publications

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“…Seemingly at variance with this scenario of transcriptional regulation is that in RAW264.7 macrophages, LPS-induced downregulation of TLR4 mRNA has been attributed to an increase in TLR4 mRNA turnover (Roger et al, 2005). LPS is known to activate the PI3K/Akt pathway (Guha and Mackman, 2002) and this event may, through inactivation of MAPK p38 (Fukao and Koyasu, 2003), decrease mRNA stability at the 3 -UTR region of a variety of genes (Dean et al, 2004). In favor of this mechanism is our finding that inhibtion of the PI3K/Akt pathway enhances NF-B activation as well as the LPS-mediated downregulation of TLR4 and TLR5 mRNA and upregulation of TLR2 and MIP-2 mRNA (Fig.…”

Section: Discussionmentioning

confidence: 99%

Ligand-induced differential cross-regulation of Toll-like receptors 2, 4 and 5 in intestinal epithelial cells

Aubel

Keestra

Krooshoop

et al. 2007

Molecular Immunology

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Toll-like receptors (TLR) 2, TLR4 and TLR5 are primary mucosal sensors of microbial patterns. Dissection of the cross-talk between TLRs in intestinal cells has thus far been hampered by the lack of functional TLR2 and TLR4 in in vitro model systems. Here we report that the mouse intestinal epithelial cell line mIC cl2 expresses these TLRs and that receptor expression and function are regulated by environmental TLR stimuli. Our results show that stimulation of TLR5 by bacterial flagellin resulted in upregulated TLR2 and TLR4 mRNA and concomitant sensitization of the cells for subsequent TLR2 (Pam 3 CSK 4 ) and TLR4 (LPS) stimulation. Exposure to low amounts of either Pam 3 CSK 4 or LPS in turn downregulated TLR5 mRNA and attenuated subsequent flagellin-mediated NF-B activation, pointing to a negative feedback mechanism. Pam 3 CSK 4 and LPS also downregulated TLR4 mRNA but upregulated TLR2 mRNA and sensitized cells for subsequent TLR2 stimulation. Inhibition of the phosphatidylinositol-3-kinase/Akt pathway only affected LPS-mediated TLR cross-talk indicating that differential TLR cross-regulation was conferred via different mechanisms. Together, our results demonstrate that the expression and function of TLR in intestinal cells are highly dynamic and tightly regulated in response to encountered bacterial stimuli.

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Section: Discussionmentioning

confidence: 99%

Ligand-induced differential cross-regulation of Toll-like receptors 2, 4 and 5 in intestinal epithelial cells

Aubel

Keestra

Krooshoop

et al. 2007

Molecular Immunology

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“…Two kinases that have been particularly implicated in mRNA-stabilizing effects are p38 and PKC [39,40]. Importantly, both can be activated by IL-1β and have been convincingly implicated in COX-2 mRNA stabilization [21,31,[41][42][43][44][45][46].…”

Section: Page 14 Of 48mentioning

confidence: 99%

IL-1β potently stabilizes IL-6 mRNA in human astrocytes

Spooren

Mestdagh

Rondou

et al. 2011

Biochemical Pharmacology

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Uncontrolled expression of IL-6 in the central nervous system is associated with neurodegenerative pathology and glioma development. Astrocytes are the predominant source of IL-6 in the central nervous system, and they are characteristically susceptible to synergistic IL-6 expression. Combined β-adrenergic and TNF-receptor triggering induces synergistic IL-6 expression in 1321N1 cells via a transcriptional enhancer mechanism. Here, we have investigated the molecular basis of the very potent "super"-synergistic IL-6 expression that is apparent after combined treatment of astrocytes with a β-adrenergic agonist, isoproterenol, and the inflammatory cytokines TNF-α and IL-1β. We found that IL-1β treatment strengthens the IL-6 synergy by inducing a distinct stabilization of IL-6 mRNA. Surprisingly, the mRNAstabilizing effect seems to be dependent on protein kinase C (PKC), but not on the prototypical mRNA-stabilizing kinase p38. Moreover, although the mRNA-binding protein HuR basally stabilizes IL-6 mRNA, the mRNA-stabilizing effect of IL-1β is independent of HuR. Our data using pharmacological inhibitors suggest PKC is an important modulator of IL-6 expression in the central nervous system and this might have therapeutic implications.

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“…ARE-AREBP complexes also mediate the post-transcriptional regulation of mRNA stability by signal transduction pathways. For example many ARE-containing inflammatory mRNAs are unstable in the absence of an appropriate stimulus, but are transiently stabilized following the activation of the p38 mitogen-activated protein kinase (MAPK) pathway Dean et al, 2004), which brings about the phosphorylation and inactivation of TTP (Stoecklin et al, 2004). An unusual mechanism exists for the GC-induced destabilization of CCL2…”

Section: A Clarkmentioning

confidence: 99%

“…The substrate selectivity of DUSP1 is not fully understood (Abraham and Clark, 2006). The MAPKs regulate inflammatory gene expression at both transcriptional and post-transcriptional levels via the phosphorylation of transcription factors and RNA binding proteins Dean et al, 2004;Ip and Davis, 1998;Kracht and Saklatvala, 2002;Ono and Han, 2000). DUSP1 is induced by pro-inflammatory stimuli and forms a negative feedback loop to limit MAPK signaling and the expression of inflammatory mediators.…”

Section: Dusp1mentioning

confidence: 99%