Upregulation of CCAAT/enhancer binding protein β in activated astrocytes and microglia

Ejarque-Ortíz, Aroa; Medina, Manel G.; Tusell, Josep Maria; Pérez-González, Anna P.; Serratosa, Joan; Saura, Josep

doi:10.1002/glia.20446

Cited by 88 publications

(102 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Engagement of these pathways has been shown to occur upon ligation with the MIF receptor, CD74 (61). There is an emerging role for the transcription factor C/ EBP-b, as it has been shown to mediate mechanisms of neuroinflammation through its activity on myeloid cell function (42,(46)(47)(48). Of interest, C/EBP-b binding sites have been identified in the promoter regions of several inflammatory cytokines, including TNF-a, IL-1b, IL-6, and MIP-1a (42,47).…”

Section: Discussionmentioning

confidence: 99%

“…There is an emerging role for the transcription factor C/ EBP-b, as it has been shown to mediate mechanisms of neuroinflammation through its activity on myeloid cell function (42,(46)(47)(48). Of interest, C/EBP-b binding sites have been identified in the promoter regions of several inflammatory cytokines, including TNF-a, IL-1b, IL-6, and MIP-1a (42,47). In the setting of adipogenesis, MIF has previously been shown to play a role in regulating adipocytes through modulation of C/EBP family members (62).…”

Section: Discussionmentioning

confidence: 99%

“…The diversity of MIF-mediated responses suggests that its activities are connected to a complex signaling cascade. Of interest, the C/ EBP family of transcription factors has received increasing attention for their role in neuroinflammation and, more specifically, their ability to regulate myeloid cell effector function (42,(46)(47)(48). Interestingly, C/EBP-b gene expression was dose dependently increased in primary microglia following MIF treatment (Fig.…”

Section: Cultured Microglia Are Responsive To Mifmentioning

confidence: 98%

“…RNA was reverse transcribed using SuperScript II and random primers (Invitrogen) to obtain cDNA. Quantitative real-time PCR analysis was conducted by using specific primers for TNF-a, IL-1b, IL-6, inducible NO synthase (iNOS), MCP-1, MIP-1a, and MIP-1b, as previously described (41,42). The following primers were used to amplify mRNA: C/EBP-a (forward, 59-TGGACAAGAACAGCAACGAGTAC-39; reverse, 59-GCAGTTGCCCAT-GGCCTTGAC-39) and C/EBP-b (forward, 59-GGTTTCGGGACTTGAT-GCA-39; reverse, 59-CAACAACCCCGCAGGAAC-39).…”

Section: Rna Preparation and Quantitative Real-time Pcrmentioning

confidence: 99%

See 3 more Smart Citations

Macrophage Migration Inhibitory Factor Potentiates Autoimmune-Mediated Neuroinflammation

Cox

Kithcart

Pitt

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

Macrophage migration inhibitory factor (MIF) is a multipotent cytokine that is associated with clinical worsening and relapses in multiple sclerosis (MS) patients. The mechanism through which MIF promotes MS progression remains undefined. In this study, we identify a critical role for MIF in regulating CNS effector mechanisms necessary for the development of inflammatory pathology in a mouse model of MS, experimental autoimmune encephalomyelitis (EAE). Despite the ability to generate pathogenic myelin-specific immune responses peripherally, MIF-deficient mice have reduced EAE severity and exhibit less CNS inflammatory pathology, with a greater percentage of resting microglia and fewer infiltrating inflammatory macrophages. We demonstrate that MIF is essential for promoting microglial activation and production of the innate soluble mediators IL-1β, IL-6, TNF-α, and inducible NO synthase. We propose a novel role for MIF in inducing microglial C/EBP-β, a transcription factor shown to regulate myeloid cell function and play an important role in neuroinflammation. Intraspinal stereotaxic microinjection of MIF resulted in upregulation of inflammatory mediators in microglia, which was sufficient to restore EAE-mediated inflammatory pathology in MIF-deficient mice. To further implicate a role for MIF, we show that MIF is highly expressed in human active MS lesions. Thus, these results illustrate the ability of MIF to influence the CNS cellular and molecular inflammatory milieu during EAE and point to the therapeutic potential of targeting MIF in MS.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Cultured Microglia Are Responsive To Mifmentioning

confidence: 98%

Section: Rna Preparation and Quantitative Real-time Pcrmentioning

confidence: 99%

See 2 more Smart Citations

Macrophage Migration Inhibitory Factor Potentiates Autoimmune-Mediated Neuroinflammation

Cox

Kithcart

Pitt

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…2 A previous report showed that SP600125 inhibited expression of C/EBP␤ in LPS-stimulated microglia. 18 ER stress possibly induces expression of C/EBP␤ via activation of the IRE1-JNK pathway.…”

Section: Discussionmentioning

confidence: 99%

ER Stress Depresses NF-κB Activation in Mesangial Cells through Preferential Induction of C/EBPβ

Hayakawa

Nakajima

Hiramatsu

et al. 2010

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Modest induction of endoplasmic reticulum (ER) stress confers resistance to inflammation in glomeruli. Recently, we found that ER stress leads to mesangial insensitivity to cytokine-induced activation of NF-B, but the underlying mechanisms are incompletely understood. ER stress can trigger expression of CCAAT/enhancer-binding proteins (C/EBPs), which interact with transcription factors including NF-B. Here, we investigated a role for C/EBPs in the ER stress-induced resistance to cytokines. Mesangial cells preferentially induced C/EBP␤ after exposure to thapsigargin or tunicamycin; induction of C/EBP␦ was modest and transient, and expression of C/EBP␣ was absent. The induction of C/EBP␤ correlated with accumulation of C/EBP␤ protein and enhanced transcriptional activity of C/EBP. Overexpression of C/EBP␤ markedly suppressed TNF-␣-induced activation of NF-B, independent of its transacting potential. Knockdown of C/EBP␤ by small interfering RNA reversed the suppressive effect of ER stress on NF-B. In vivo, preconditioning of mice with ER stress induced renal C/EBP␤ and suppressed NF-Bdependent gene expression in response to LPS. Using dominant negative mutants and null mutants for individual branches of the unfolded protein response, we identified the RNA-dependent protein kinaselike ER kinase (PERK) and the inositol-requiring ER-to-nucleus signal kinase 1 (IRE1) pathways as the unfolded protein response responsible for ER stress-induced C/EBP␤. These results suggest that ER stress blunts cytokine-triggered activation of NF-B, in part through PERK-and IRE1-mediated preferential induction of C/EBP␤.

show abstract

Spatiotemporal nuclear factor interleukin‐6 expression in the rat brain during lipopolysaccharide‐induced fever is linked to sustained hypothalamic inflammatory target gene induction

Damm

Luheshi

Gerstberger

et al. 2010

J of Comparative Neurology

View full text Add to dashboard Cite

Rats injected with lipopolysaccharide (LPS) show brain-controlled sickness symptoms, including fever. In these animals, early genomic activation of brain cells was previously monitored by immunohistochemical detection of transcription factors such as nuclear factor (NF)-κB or signal transducer and activator of transcription (STAT)3 and was linked to the initiation or maintenance of the febrile response. To investigate whether NF-IL6 might be another important transcription factor implicated in this kind of immune-to-brain signaling, rats were injected with LPS (100 μg/kg, intraperitoneally) or phosphate-buffered saline, and brains were analyzed by immunohistochemistry, real-time PCR, or Western blot 4, 6, 8, and 10 hours later. Moderate to strong LPS-induced nuclear NF-IL6 immunoreactivity (IR) occurred in a time-dependent manner within circumventricular organs, namely, the vascular organ of the lamina terminalis, the subfornical organ, the area postrema, and the median eminence, brain structures with a leaky blood-brain barrier. Furthermore, nuclear NF-IL6-IR was observed in the pituitary gland, the choroid plexus, and the meninges as well as blood vessels throughout the entire brain. Endothelial, microglial, and ependymal cells, astrocytes, perivascular macrophages, and neurons exhibited LPS-induced nuclear NF-IL6-IR; mRNA levels of NF-IL6, responsive inflammatory genes, and NF-IL6 protein levels were significantly elevated. As opposed to observations on STAT3 or NFκB, the percentage of NF-IL6-reactive cells increased in parallel to late phases of the febrile response. In conclusion, these results suggest a potential role for NF-IL6 in the maintenance or possibly the termination of LPS-induced fever. Moreover, we propose NF-IL6 to be a delayed brain cell activation marker.

show abstract

Upregulation of CCAAT/enhancer binding protein β in activated astrocytes and microglia

Cited by 88 publications

References 52 publications

Macrophage Migration Inhibitory Factor Potentiates Autoimmune-Mediated Neuroinflammation

Macrophage Migration Inhibitory Factor Potentiates Autoimmune-Mediated Neuroinflammation

ER Stress Depresses NF-κB Activation in Mesangial Cells through Preferential Induction of C/EBPβ

Spatiotemporal nuclear factor interleukin‐6 expression in the rat brain during lipopolysaccharide‐induced fever is linked to sustained hypothalamic inflammatory target gene induction

Contact Info

Product

Resources

About