Decreased brain damage and curtailed inflammation in transcription factor CCAAT/enhancer binding protein β knockout mice following transient focal cerebral ischemia

Kapadia, Ramya; Türeyen, Kudret; Bowen, Kellie K.; Kalluri, Haviryaji S. G.; Johnson, Peter F.; Vemuganti, Raghu

doi:10.1111/j.1471-4159.2006.04056.x

Cited by 103 publications

(114 citation statements)

References 58 publications

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“…For example, as C/EBPb promotes neutrophil activation and heightened inflammation, it is not surprising that C/EBPb lossof-function is neuroprotective after focal stroke. 36 This observation does not however negate the possibility that C/EBPb could have entirely different effects on cell autonomous survival and repair of neurons. It is likely that differences in the mechanism of injury, severity of the stimulus and timing will determine which of these opposing activities dominate within ischemia-sensitive structures like the CA1 field of the hippocampus.…”

Section: Resultsmentioning

confidence: 76%

MKP-1 antagonizes C/EBP β activity and lowers the apoptotic threshold after ischemic injury

et al. 2012

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The dual specificity phosphatase MAPK phosphatase-1 (MKP-1) feeds back on MAP kinase signaling to regulate metabolic, inflammatory and survival responses. MKP-1 is widely expressed in the central nervous system (CNS) and induced after ischemic stress, although its function in these contexts remains unclear. Here we report that MKP-1 activated several cell death factors, including BCL2 and adenovirus E1B 19 kDa interacting protein 3, and caspases 3 and 12 culminating in apoptotic cell death in vitro. MKP-1 also exerted inhibitory effects on the bZIP transcription factor CCAAT/enhancer-binding protein (C/EBPb), previously shown to have neuroprotective properties. These effects included reduced expression of the full-length C/EBPb variant and hypo-phosphorylation at the MEK-ERK1/2-sensitive Thr 188 site. Notably, enforced expression C/EBPb rescued cells from MKP-1-induced toxicity. Studies performed in knock-out mice indicate that the MKP-1 activity is required to exclude C/EBPb from the nucleus basally, and that MKP-1 antagonizes C/EBPb expression after global forebrain ischemia, particularly within the vulnerable CA1 sector of the hippocampus. Overall, MKP-1 appears to lower the cellular apoptotic threshold by inhibiting C/EBPb and enhancing both BH3 protein expression and cellular caspase activity. Thus, although manipulation of the MKP-1-C/EBPb axis could have therapeutic value in ischemic disorders, our observations using MKP-1 catalytic mutants suggest that approaches geared towards inhibiting MKP-1's phosphatase activity alone may be ineffective.

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Section: Resultsmentioning

confidence: 76%

MKP-1 antagonizes C/EBP β activity and lowers the apoptotic threshold after ischemic injury

et al. 2012

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“…Although Cebpb expression is generally induced in response to physiological stress, including hypoxia and inflammation in several tissues and cell types, Cebpb Ϫ/Ϫ mice in which C/EBP␤-dependent gene regulation has been abrogated display a paradoxically improved response to both ischemic stroke (28) and inflammatory steatohepatitis (29), presumably because both the pro-and antiinflammatory effects of C/EBP␤ action have been blocked systemically. More subtle perturbations, such as the one used in the present study, will be necessary to tease out various tissue-specific and …”

Section: Discussionmentioning

confidence: 99%

A CREB-C/EBPβ cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair

Ruffell

Mourkioti²,

Gambardella³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

542

439

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Macrophages play an essential role in the resolution of tissue damage through removal of necrotic cells, thus paving the way for tissue regeneration. Macrophages also directly support the formation of new tissue to replace the injury, through their acquisition of an anti-inflammatory, or M2, phenotype, characterized by a gene expression program that includes IL-10, the IL-13 receptor, and arginase 1. We report that deletion of two CREB-binding sites from the Cebpb promoter abrogates Cebpb induction upon macrophage activation. This blocks the downstream induction of M2-specific Msr1, Il10, II13ra, and Arg-1 genes, whereas the inflammatory (M1) genes Il1, Il6, Tnfa, and Il12 are not affected. Mice carrying the mutated Cebpb promoter (␤⌬Cre) remove necrotic tissue from injured muscle, but exhibit severe defects in muscle fiber regeneration. Conditional deletion of the Cebpb gene in muscle cells does not affect regeneration, showing that the C/EBP␤ cascade leading to muscle repair is muscle-extrinsic. While ␤⌬Cre macrophages efficiently infiltrate injured muscle they fail to upregulate Cebpb, leading to decreased Arg-1 expression. CREB-mediated induction of Cebpb expression is therefore required in infiltrating macrophages for upregulation of M2-specific genes and muscle regeneration, providing a direct genetic link between these two processes.macrophage polarization ͉ muscle regeneration ͉ transcription

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“…SOCS acts as a negative feedback regulator and inhibits further JAK and STAT phosphorylation, thus preventing the upregulation and binding of cytokines to their receptors after an acute CNS insult (33,67). Our recent studies showed that focal ischemia induces a massive upregulation of IL-6, which increases the phosphorylation of the JAK2 and STAT3 isoforms in the ischemic hemisphere (68,69,123). Although physiological levels of STAT3 activation are essential for normal cellular functions, its excessive phosphorylation as seen after focal cerebral ischemia is neurotoxic.…”

Section: Ppar-gamma-independent-mechanismsmentioning

confidence: 99%

“…Transcriptional activation can be viewed as a double-edged sword since individual transcription factors can induce either neuroprotective or neurotoxic genes. Recent studies have shown that transcription factors like interferon regulatory factor (IRF)-1, signal transducer and activator of transcription (STAT)-3, nuclear factor (NF)-kappaB, CCAAT/ enhancer binding protein (C/EBP)-beta and early growth response (EGR)-1 promote inflammatory gene expression and thus precipitates severe neuronal damage (60,69,123,128,129). On the other hand, the activation of transcription factors like nuclear factor-E2 related factor (Nrf)-2, peroxisome proliferator-activated receptor (PPAR)-alpha and PPAR-gamma, cAMP response element-binding protein (CREB) and hypoxia-inducible factor (HIF)-1 have been suggested to be neuroprotective since they curtail oxidative stress and inflammatory gene expression (33,52,107,114,122).…”

Section: Role Of Transcription Factors In Post-ischemic Inflammationmentioning

confidence: 99%

Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists

Kapadia

Yi²,

Vemuganti³

2008

Front Biosci

Self Cite

374

246

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Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily. The 3 PPAR isoforms (alpha, delta/beta and gamma) are known to control many physiological functions including glucose absorption, lipid balance, and cell growth and differentiation. Of interest, PPAR-gamma activation was recently shown to mitigate the inflammation associated with chronic and acute neurological insults. Particular attention was paid to test the therapeutic potential of PPAR agonists in acute conditions like stroke, spinal cord injury (SCI) and traumatic brain injury (TBI), in which massive inflammation plays a detrimental role. While 15d-prostaglandin J2 (15d PGJ 2 ) is the natural ligand of PPAR-gamma, the thiazolidinediones (TZDs) are potent exogenous agonists. Due to their insulin-sensitizing properties, 2 TZDs rosiglitazone and pioglitazone are currently FDA-approved for type-2 diabetes treatment. Recent studies from our laboratory and other groups have shown that TZDs induce significant neuroprotection in animal models of focal ischemia and SCI by multiple mechanisms. The beneficial actions of TZDs were observed to be both PPAR-gamma-dependent as well as -independent. The major mechanism of TZD-induced neuroprotection seems to be prevention of microglial activation and inflammatory cytokine and chemokine expression. TZDs were also shown to prevent the activation of pro-inflammatory transcription factors at the same time promoting the anti-oxidant mechanisms in the injured CNS. This review article discusses the multiple mechanisms of TZDinduced neuroprotection in various animal models of CNS injury with an emphasis on stroke. KeywordsTranscription Factor; Inflammation; Brain Damage; Nuclear Factor; Cerebral Ischemia; Stroke; Neuroprotection; Review INTRODUCTIONStroke is the leading cause of long-term disability in the adult population worldwide. A variety of pathophysiological processes contribute to the irreversible neuronal injury that eventually results in neurological dysfunction after stroke. The complex nature of these processes involves specific cell types that effect several downstream signalling pathways. In a majority of stroke patients, only a small area of the brain tissue, the ischemic core, is irreversibly damaged. A much larger volume of the brain tissue surrounding the ischemic core, called the penumbra, can potentially recover if treatment is provided in a timely manner (3). Tissue protection and regeneration are tightly regulated by cell growth, survival and cell death signals provided by the cellular microenvironment. Hence, understanding the molecular mechanisms that govern Send correspondence to: Dr. Raghu Vemuganti, Department of Neurological Surgery, K4/8 Mail code CSC 8660, 600 Highland Avenue, Madison, WI 53792, Tel:608-263-4055, Fax:608-263-1728, E-mail: vemugant@neurosurg.wisc.edu. NIH Public Access Author ManuscriptFront Biosci. Author manuscript; available in PMC 2009 August 28. Published in final edited form as:Fr...

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Decreased brain damage and curtailed inflammation in transcription factor CCAAT/enhancer binding protein β knockout mice following transient focal cerebral ischemia

Cited by 103 publications

References 58 publications

MKP-1 antagonizes C/EBP β activity and lowers the apoptotic threshold after ischemic injury

MKP-1 antagonizes C/EBP β activity and lowers the apoptotic threshold after ischemic injury

A CREB-C/EBPβ cascade induces M2 macrophage-specific gene expression and promotes muscle injury repair

Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists

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