Age-related changes in the regulation of transcription factor NF-κB in rat brain

Korhonen, Pauliina; Helenius, Merja; Salminen, Antero

doi:10.1016/s0304-3940(97)00190-0

Cited by 122 publications

(79 citation statements)

References 17 publications

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“…Numerous studies have proposed that LPS could induce the activation of NF-κB, contributing to the upregulated expression of several genes in macrophages Shakhov et al 1990). Moreover, NF-κB DNA binding activity is altered in the rat liver and brain and mouse macrophages with aging (Korhonen et al 1997;Radak et al 2004;Sarkar and Fisher 2006), indicating that NF-κB might be involved in modulating the differentially expressed miR-101b and miR-26b. Data from this study show that IκBα phosphorylation inhibitor BAY 11-7082 suppressed miR-101b and miR-26b expression in young macrophages.…”

Section: Tsa Suppresses Cox-2 Protein Expression By Upregulation Of Mmentioning

confidence: 99%

Dysregulated expression of miR-101b and miR-26b lead to age-associated increase in LPS-induced COX-2 expression in murine macrophage

Liú

Wang

et al. 2015

AGE

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Aging is the natural process of decline in physiological structure and function of various molecules, cells, tissues, and organs. Growing evidence indicates that increased immune genetic diversity and dysfunction of immune system cause aging-related pathophysiological process with the growth of age. In the present study, we observed that LPS-induced higher activation of cyclooxygenase (COX)-2 promoter is associated with the upregulated binding activity of nuclear factor kappa B (NF-κB) in peritoneal macrophages of aged mice than young ones. Additionally, COX-2 is a direct target of miR-101b and miR-26b in the macrophages. Significant upregulation of miR-101b and miR26b effectively prevented LPS-induced excessive expression of COX-2 in the young mice. Because these negative regulatory factors were unresponsive to LPS stimulation, the levels of COX-2 were markedly higher in the macrophages of aged mice. Further study showed that NF-κB activation contributed to the increase in the expression of miR-101b and miR-26b in the LPSstimulated macrophages of young mice, but not aged ones. Moreover, histone deacetylase (HDAC) inhibitor trichostatin A (TSA) upregulated expression of miR101b and miR-26b in the aged mouse macrophages only, but not the young cells. This demonstrated that HDAC suppressed the expression of miR-101b and miR-26b in the LPS-treated macrophages of aged mice and contributed to the aging process. TSA-induced increased expression of miR-101b and miR-26b could further suppress COX-2 expression. These findings provide novel evidence on the regulation of immune senescence and miR-101b and miR-26b, which might be promising targets in treating aged-related inflammatory diseases. Epigenetic regulation of the microRNAs (miRNAs) provides an important evidence for the treatment of innate inflammatory disease with HDAC inhibitors in elderly.

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Section: Tsa Suppresses Cox-2 Protein Expression By Upregulation Of Mmentioning

confidence: 99%

Dysregulated expression of miR-101b and miR-26b lead to age-associated increase in LPS-induced COX-2 expression in murine macrophage

Liú

Wang

et al. 2015

AGE

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“…Of the transcription factors found in the promoter region of the COX-2 gene, NF-B is the most intensively studied and several investigations have linked its activity to the activation of the COX-2 gene (16,18). Although the age-related up-regulation of NF-B activation has been shown in rat gastric mucosa (33), kidney (34), liver, heart (35), and brain (36), its binding activity in M, a major source of PGE 2 , has not been compared between young and old animals. In this study, the peritoneal M from young and old mice were stimulated with LPS for different times as indicated in Fig.…”

Section: Nf-b Binding Activity In Murine M Increases With Ag-mentioning

confidence: 99%

Ceramide-induced and Age-associated Increase in Macrophage COX-2 Expression Is Mediated through Up-regulation of NF-κB Activity

Wu¹,

Marko²,

Claycombe³

et al. 2003

Journal of Biological Chemistry

104

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We have shown that the age-associated increase in lipopolysaccharide (LPS)-stimulated macrophages (M) prostaglandin E 2 (PGE 2 ) production is because of ceramide-induced up-regulation of cyclooxygenase (COX)-2 transcription that leads to increased COX-2 expression and enzyme activity. To determine the mechanism of the age-related and ceramide-dependent increase in COX-2 transcription, we investigated the role of various transcription factors involved in COX-2 gene expression. The results showed that LPS-initiated activations of both consensus and COX-2-specific NF-B, but not AP-1 and CREB, were significantly higher in M from old mice than those from young mice. We further showed that the higher NF-B activation in old M was because of greater IB degradation in the cytoplasm and p65 translocation to the nucleus. An IB phosphorylation inhibitor, Bay 11-7082, inhibited NF-B activation, as well as PGE 2 production, COX activity, COX-2 protein, and mRNA expression in both young and old M. Similar results were obtained by blocking NF-B binding activity using a NF-B decoy. Furthermore, NF-B inhibition resulted in significantly greater reduction in PGE 2 production and COX activity in old compared with young M. Addition of ceramide to the young M, in the presence or absence of LPS, increased NF-B activation in parallel with PGE 2 production. Bay 11-7082 or NF-B decoy prevented this ceramide-induced increase in NF-B binding activity and PGE 2 production. These findings strongly suggest that the age-associated and ceramide-induced increase in COX-2 transcription is mediated through higher NF-B activation, which is, in turn, because of a greater IB degradation in old M.It is well documented that T cell-mediated immune function declines in old animals and elderly humans compared with their young counterparts (1, 2). The age-associated dysregulation in macrophages (M) 1 contributes to the impaired T cell function with aging. We, as well as others, have demonstrated that immune cells, including M, from old animals and humans produced more PGE 2 than those from their young counterparts (3-7). We further showed that the increased PGE 2 production by M contributes to the decline in T cell-mediated function with aging (8).Cyclooxygenase (COX) is the rate-limiting enzyme that catalyzes the conversion of arachidonic acid (AA) to PG endoperoxide (PGH 2 ), which is further converted to different PGs and thromboxane. COX is hence a key factor in PG synthesis. Two isoforms of COX have been identified: a constitutive form, COX-1 (9, 10), and the inducible counterpart, COX-2 (11, 12). We have demonstrated that the age-associated increase in M PGE 2 production is because of higher COX activity in M from old mice compared with those from young mice. This increased COX activity is, in turn, a result of increased expression of COX-2 protein and mRNA (13). In a recent study, we further demonstrated that the age-related increase in COX-2 mRNA was because of a higher level of ceramide in old M compared with those of young, which induced up-regu...

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“…For example, although many mammalian cells express low levels of active NF-B, other cell types such as B cells, thymocytes, macrophages, neurons of the cortex and hippocampus, and cultured proliferating smooth muscle cells have been found to express relatively high basal levels of NF-B (15)(16)(17)(18)(19)(20)(21)(22). In addition, elevation of constitutive NF-B activity has been reported for several different types of tumor cell, in aged animals and during the terminal differentiation of monocyte-derived dendritic cells (22)(23)(24)(25)(26). The mechanisms that regulate basal NF-B activity in cells are relatively poorly understood.…”

mentioning

confidence: 98%

Basal Expression of IκBα Is Controlled by the Mammalian Transcriptional Repressor RBP-J (CBF1) and Its Activator Notch1

Oakley

Mann

Ruddell

et al. 2003

Journal of Biological Chemistry

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By using the hepatic stellate cell (HSC) as a paradigm for cells that undergo long term re-programming of NF-B-dependent transcription, we have determined a novel mechanism by which mammalian cells establish their basal NF-B activity. Elevation of NF-B activity during HSC activation is accompanied by induction of CBF1 expression and DNA binding activity. We show that the transcriptional repressor CBF1 interacts with a dual NF-B/CBF1-binding site (B2) in the IB␣ promoter. Nucleotide substitutions that disrupt CBF1 binding to the B2 site result in an elevation of IB␣ promoter activity and loss of responsiveness of the promoter to a transfected CBF1 reporter vector. Overexpression of CBF1 in COS1 cells was associated with markedly reduced IB␣ protein expression and elevated NF-B DNA binding activity. CBF1-induced repression of IB␣ promoter activity was reversed in HSC transfected with the Notch1 intracellular domain (NICD). The ability of NICD to enhance IB␣ gene transcription was confirmed in COS1 cells and was found to be dependent on an intact RAM domain of NICD that has been shown previously to help mediate the interaction of NICD with CBF1. One of the mechanisms by which NICD is thought to convert CBF1 into an activator of transcription is via the recruitment of transcriptional co-activators/histone acetylases to gene promoters. Co-transfection of HSC with NICD and p53 caused a diminution of IB␣ promoter activity, by contrast overexpression of p300 enhanced IB␣ promoter function. Taken together, these data suggest that basal IB␣ expression (and as a consequence NF-B activity) is under the control of the various components of the CBF1/Notch signal transduction pathway.The transcription factor NF-B is a key regulator of the growth, differentiation, and fate of mammalian cells (1). In its active form NF-B is found in the nucleus as either a heterodimer or a homodimer composed of five different members of the Rel family of proteins (p65, p50, p52, c-Rel, and RelB) (1). Active NF-B can bind to its target DNA sequence (GGGRN-NYYCC) and activate the transcription of a vast number and wide range of genes (2). Given the importance of NF-B as a regulator of cell function, it is essential that its transcriptional activity is subject to exquisite control mechanisms. Most cells only express low levels of basal nuclear NF-B activity, with the majority of Rel dimers being sequestered in the cytoplasm in a complex with an inhibitory IB protein. The three most important IB proteins, IB␣, IB␤, and IB⑀, inhibit NF-B function by masking nuclear localization and DNA binding signals (1, 3). These inhibitors are pivotal regulators of NF-Bdependent gene expression as they can be degraded in response to a wide variety of epigenetic stimulators and in doing so release active NF-B which can then translocate to the nucleus and activate transcription (3). Perturbation of IB control of NF-B has been associated with many pathological conditions including chronic inflammatory diseases, persistence of viral infections, and cancer (4 -7). Ther...

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Age-related changes in the regulation of transcription factor NF-κB in rat brain

Cited by 122 publications

References 17 publications

Dysregulated expression of miR-101b and miR-26b lead to age-associated increase in LPS-induced COX-2 expression in murine macrophage

Dysregulated expression of miR-101b and miR-26b lead to age-associated increase in LPS-induced COX-2 expression in murine macrophage

Ceramide-induced and Age-associated Increase in Macrophage COX-2 Expression Is Mediated through Up-regulation of NF-κB Activity

Basal Expression of IκBα Is Controlled by the Mammalian Transcriptional Repressor RBP-J (CBF1) and Its Activator Notch1

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