Distinct role of MAPKAPK-2 in the regulation of TNF gene expression by Toll-like receptor 7 and 9 ligands

Thuraisingam, Thusanth; Xu, Yong; Moisan, Jacques; Lachance, Claude; Garnon, James; Marco, Sergio Di; Gaestel, Matthias; Radzioch, Danuta

doi:10.1016/j.molimm.2007.03.019

Cited by 24 publications

(25 citation statements)

References 34 publications

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“…Based on these results and the work of others showing that MK2, a direct substrate for p38 MAPK, can mediate cytotoxic effects after injury or disease (Wang et al, 2002;Culbert et al, 2006;L. Xu et al, 2006;Thuraisingam et al, 2007;Thomas et al, 2008), we analyzed pMK2 levels after SCI. We see that as early as 12 h after SCI, pMK2 is expressed in neurons and astrocytes.…”

Section: Discussionmentioning

confidence: 99%

“…Seven days after SCI, pMK2 expression is seen primarily in macrophages/microglia, neurons, and some astrocytes. MK2 has previously been shown to play an important role in regulating proinflammatory chemokine and cytokine expression in macrophages in vitro (Culbert et al, 2006;Thuraisingam et al, 2007). This effect may be mediated by MK2-dependent phosphorylation of proteins binding to AU-rich elements in the 3Ј untranslated region (UTR) of cytokine mRNAs, such as TTP (Mahtani et al, 2001;Chrestensen et al, 2004), which stabilizes the transcript and allows for efficient translation of the protein, leading to the increased production of proinflammatory cytokines, including TNF-␣ (Winzen et al, 1999;Mahtani et al, 2001;Neininger et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…ϩ/ϩ and MK2 Ϫ/Ϫ macrophage cell lines (Thuraisingam et al, 2007) were then plated into 24-well plates (5 ϫ 10 5 cells per well) and incubated overnight at 37°C. Twenty micrograms of DiI-labeled myelin was added to the wells for 1 h at 37°C.…”

Section: Methodsmentioning

confidence: 99%

“…Previous work from our group and others has shown that activated MK2 Ϫ/Ϫ macrophages show reduced expression of proinflammatory cytokines and nitric oxide in vitro (Lehner et al, 2002;Thuraisingam et al, 2007). We therefore assessed whether these macrophages still retain their capacity to phagocytose myelin.…”

Section: Macrophages Lacking Mk2 Retain Their Capacity To Phagocytosementioning

confidence: 96%

“…MK2 is activated by phosphorylation (Gaestel, 2006), resulting in the increased production and activation of matrix metalloproteinases (MMPs) (L. , proinflammatory cytokines (Kotlyarov et al, 1999;Winzen et al, 1999), and nitric oxide (Thuraisingam et al, 2007). MK2 knock-out mice show reduced neurotoxicity and neuroinflammation in models of Parkinson's disease (Thomas et al, 2008) and cerebral ischemia (Wang et al, 2002), and in in vitro models of Alzheimer's disease (Culbert et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 (MK2) Contributes to Secondary Damage after Spinal Cord Injury

Ghasemlou¹,

López-Vales²,

Lachance³

et al. 2010

J. Neurosci.

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The inflammatory response contributes importantly to secondary tissue damage and functional deficits after spinal cord injury (SCI). In this work, we identified mitogen-activated protein kinase (MAPK)-activated protein kinase 2 (MAPKAPK2 or MK2), a downstream substrate of p38 MAPK, as a potential target using microarray analysis of contused spinal cord tissue taken at the peak of the inflammatory response. There was increased expression and phosphorylation of MK2 after SCI, with phospho-MK2 expressed in microglia/ macrophages, neurons and astrocytes. We examined the role of MK2 in spinal cord contusion injury using MK2 Ϫ/Ϫ mice. These results show that locomotor recovery was significantly improved in MK2 Ϫ/Ϫ mice, compared with wild-type controls. MK2 Ϫ/Ϫ mice showed reduced neuron and myelin loss, and increased sparing of serotonergic fibers in the ventral horn caudal to the injury site. We also found differential expression of matrix metalloproteinase-2 and 9 in MK2 Ϫ/Ϫ and wild-type mice after SCI. Significant reduction was also seen in the expression of proinflammatory cytokines and protein nitrosylation in the injured spinal cord of MK2 Ϫ/Ϫ mice. Our previous work has shown that macrophages lacking MK2 have an anti-inflammatory phenotype. We now show that there is no difference in the number of macrophages in the injured spinal cord between the two mouse strains and little if any difference in their phagocytic capacity, suggesting that macrophages lacking MK2 have a beneficial phenotype. These findings suggest that a lack of MK2 can reduce tissue damage after SCI and improve locomotor recovery. MK2 may therefore be a useful target to treat acute SCI.

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