MK2 Targets AU-rich Elements and Regulates Biosynthesis of Tumor Necrosis Factor and Interleukin-6 Independently at Different Post-transcriptional Levels

Neininger, Armin; Kontoyiannis, Dimitris L.; Kotlyarov, Alexey; Winzen, Reinhard; Eckert, R; Volk, Hans‐Dieter; Holtmann, Helmut; Kollias, George; Gaestel, Matthias

doi:10.1074/jbc.c100685200

Cited by 376 publications

(332 citation statements)

References 28 publications

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“…Relatively little is known about the signaling pathways responsible for IL-6 mRNA stabilization. It has been found by multiple groups that the mitogen-activated protein kinase (MAPK) p38 stabilizes IL-6 mRNA [12,[15][16][17][18]. Another kinase often associated with mRNA stabilization is protein kinase C (PKC).…”

Section: Page 4 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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Section: Page 4 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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“…MK2-deficient cells derived from mice have shown defects in motility, chemotaxis, and cytokine production (6 -8). Several studies using MK2-deficient mice strongly support the central role of this kinase in the production of inflammatory cytokines such as TNF-␣, IL-6, and IFN-␥ (6,9). AU-rich elements have been identified in the 3Ј untranslated region of several cytokine mRNAs (10,11) and are known to regulate mRNA stability (11,12) and translation (13).…”

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confidence: 97%

MAPKAP Kinase 2-Deficient Mice Are Resistant to Collagen-Induced Arthritis

Hegen

Gaestel

Nickerson‐Nutter

et al. 2006

The Journal of Immunology

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138

107

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TNF-α is a pleiotropic cytokine considered a primary mediator of immune regulation and inflammatory response and has been shown to play a central role in rheumatoid arthritis (RA). MAPKAP kinase 2 (MK2) is a serine/threonine kinase that is regulated through direct phosphorylation by p38 MAPK, and has been shown to be an essential component in the inflammatory response that regulates the biosynthesis of TNF-α at a posttranscriptional level. The murine model of collagen-induced arthritis (CIA) is an established disease model to study pathogenic mechanisms relevant to RA. In this study, we report that deletion of the MK2 gene in DBA/1LacJ mice confers protection against CIA. Interestingly, the MK2 heterozygous mutants display an intermediate level of protection when compared with homozygous mutant and wild-type littermates. We show that MK2−/− and MK2+/− mice exhibit decreased disease incidence and severity in the CIA disease model and reduced TNF-α and IL-6 serum levels following LPS/d-Gal treatment compared with wild-type mice. Additionally, we show that levels of IL-6 mRNA in paws of mice with CIA correlate with the disease status. These findings suggest that an MK2 inhibitor could be of great therapeutic value to treat inflammatory diseases like RA.

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“…Furthermore, inactivation of the gene for MAP kinase-activated protein kinase-2 (MAPKAPK-2) (11), a downstream target of p38, abolishes LPS-triggered TNF-␣ production and renders mice resistant to endotoxin-induced septic shock (12). Moreover, deletion of the TNF-␣ ARE bypasses the requirement of p38/MAPKAPK-2 for LPS-induced TNF-␣ production (13,14). JNK also appears to play a role in relieving the ARE-mediated translational silencing of TNF-␣ mRNA, because glucocorticoids have been shown to inhibit LPS-induced JNK activation and to reduce TNF-␣ production by macrophages (7,13,15,16).…”

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confidence: 99%

Restraint of Proinflammatory Cytokine Biosynthesis by Mitogen-Activated Protein Kinase Phosphatase-1 in Lipopolysaccharide-Stimulated Macrophages

Chen

Barnes

et al. 2002

The Journal of Immunology

268

315

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Exposure of macrophages to LPS elicits the production of proinflammatory cytokines, such as TNF-α, through complex signaling mechanisms. Mitogen-activated protein (MAP) kinases play a critical role in this process. In the present study, we have addressed the role of MAP kinase phosphatase-1 (MKP-1) in regulating proinflammatory cytokine production using RAW264.7 macrophages. Analysis of MAP kinase activity revealed a transient activation of c-Jun N-terminal kinase (JNK) and p38 after LPS stimulation. Interestingly, MKP-1 was induced concurrently with the inactivation of JNK and p38, whereas blocking MKP-1 induction by triptolide prevented this inactivation. Ectopic expression of MKP-1 accelerated JNK and p38 inactivation and substantially inhibited the production of TNF-α and IL-6. Induction of MKP-1 by LPS was found to be extracellular signal-regulated kinase dependent and involved enhanced gene expression and increased protein stability. Finally, MKP-1 expression was also induced by glucocorticoids as well as cholera toxin B subunit, an agent capable of preventing autoimmune diseases in animal models. These findings highlight MKP-1 as a critical negative regulator of the macrophage inflammatory response, underscoring its premise as a potential target for developing novel anti-inflammatory drugs.

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MK2 Targets AU-rich Elements and Regulates Biosynthesis of Tumor Necrosis Factor and Interleukin-6 Independently at Different Post-transcriptional Levels

Cited by 376 publications

References 28 publications

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

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

MAPKAP Kinase 2-Deficient Mice Are Resistant to Collagen-Induced Arthritis

Restraint of Proinflammatory Cytokine Biosynthesis by Mitogen-Activated Protein Kinase Phosphatase-1 in Lipopolysaccharide-Stimulated Macrophages

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