Transcription factor decoy for AP-1 reduces mesangial cell proliferation and extracellular matrix production in vitro and in vivo

Ahn, Jung‐Mo; Morishita, Ryuichi; Kaneda, Yasufumi; Kim, H J; Kim, Y D; Lee, H J; Lee, K U; Park, J Y; Kim, Y H; Park, K K; Chang, Young‐Chae; Yoon, Kun Ho; Kwon, Hyuk Sang; Lee, I K

doi:10.1038/sj.gt.3302236

Cited by 47 publications

(41 citation statements)

References 28 publications

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“…Blunted activation of NF-B may lead to glomerular cell apoptosis that is required for clearance of excessive mesangial cells during the resolution of mesangial proliferative glomerulonephritis (49). Similarly, lack of AP-1 activation may lead to suppression of glomerular cell proliferation (50). The attenuated activation of NF-B and AP-1 in macrophage-primed mesangial cells can also cause attenuated expression of chemokines, leading to reduction in the number of glomerular macrophages.…”

Section: Discussionmentioning

confidence: 99%

Priming of Glomerular Mesangial Cells by Activated Macrophages Causes Blunted Responses to Proinflammatory Stimuli

Hayakawa

Meng

Hiramatsu

et al. 2006

The Journal of Immunology

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Macrophage-mesangial cell interaction plays a crucial role in the pathogenesis of glomerulonephritis. Activated macrophages trigger mesangial cells to express an array of inflammation-associated genes via activation of NF-κB and AP-1. However, this inflammatory response is often transient and subsides spontaneously. We found that mesangial cells activated by bystander macrophages showed blunted responses of NF-κB to subsequent macrophage exposure. It was associated with sustained levels of IκBβ, but not IκBα. The tolerance observed was reversible and reproduced by conditioned media from activated macrophages (macrophage-conditioned medium (MφCM)). In vivo priming of mesangial cells by activated glomerular macrophages also caused the tolerance of mesangial cells. The macrophage-derived tolerance inducers were heat-labile, and multiple molecules were involved. Among inflammatory cytokines produced by macrophages, TNF-α and IL-1β were able to induce mesangial cell tolerance dose-dependently. The mesangial cell tolerance was also observed in activation of the MAPK-AP-1 pathway; i.e., phosphorylation of ERK, JNK, and p38 MAPK by macrophages was blunted when the cells were pre-exposed to MφCM. Induction of c-fos and c-jun was also abrogated in mesangial cells pre-exposed to MφCM, and the suppression was attenuated by blockade of MAPK activation during the first exposure to MφCM. These data elucidated that mesangial cells, once exposed to macrophages, become insensitive to subsequent activation by macrophages and proinflammatory stimuli. This self defense of glomerular cells may play a role in the resolution of macrophage-mediated, acute glomerulonephritis.

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Section: Discussionmentioning

confidence: 99%

Priming of Glomerular Mesangial Cells by Activated Macrophages Causes Blunted Responses to Proinflammatory Stimuli

Hayakawa

Meng

Hiramatsu

et al. 2006

The Journal of Immunology

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“…p3TP-lux (TGF-b1 promoter construct) was described previously. 45 To analyze luciferase expression, the cells were washed twice with PBS and lysed in 200 ml of 1 Â reporter lysis buffer (Promega). Each lysate (50 ml) was examined for luciferase activity by means of a commercial kit (Promega).…”

Section: Suppression Of Rat Kidney Fibrosis By Sp1 Decoy Y-m Chae Et Almentioning

confidence: 99%

Ring-Sp1 decoy oligonucleotide effectively suppresses extracellular matrix gene expression and fibrosis of rat kidney induced by unilateral ureteral obstruction

et al. 2005

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Tubulointerstitial fibrosis is the consequence of an injury characterized by the accumulation of excess collagen and other extracellular matrix components, resulting in the destruction of the normal kidney architecture and subsequent loss of function. A transcription factor Sp1, originally described as a ubiquitous transcription factor, is involved in the basal expression of extracelluar matrix genes and may, therefore, be important in fibrotic processes. Here, we report on the design of a ring-Sp1 decoy oligonucleotide, containing the consensus Sp1 binding sequence in a single decoy molecule without an open end, to create a novel therapeutic strategy for fibrosis. The ring-Sp1 decoy oligonucleotide is highly resistant to degradation by nucleases or serum compared to the conventional phosphorothioated doublestranded Sp1 decoy oligonucleotide, and effectively suppressed the expression of transforming growth factor-b1 and fibronectin, the binding of Sp1 to the promoter region of these genes, and proliferation in response to serum in normal rat kidney fibroblasts. Moreover, treatment with the ring-Sp1 decoy in vivo significantly attenuates extracellular matrix gene expression in the rat kidney in which a unilateral ureteral obstruction had been induced. These results suggest that the ring-Sp1 decoy oligonucleotide represents promising therapeutic alternative to the conventional treatment of fibrotic disorders.

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“…We previously reported that an AP-1 decoy oligonucleotide which specifically binds intracellular AP-1 inhibits AP-1 transcription and cell invasion as effectively as ascochlorin [20]. We have shown that our decoy strategy effectively inhibits specific transcription factor activity and pathogenic disorders in vivo [35]. A genetic strategy targeting AP-1 activity also might be effective for treatment of ERnegative breast cancers.…”

Section: Discussionmentioning

confidence: 99%

Aberrant Expression of Fra-1 in Estrogen Receptor-negative Breast Cancers and Suppression of their Propagation In Vivo by Ascochlorin, an Antibiotic that Inhibits Cellular Activator Protein-1 Activity

et al. 2007

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Estrogen receptor-negative breast cancers generally are highly malignant, resistant to chemotherapy and poorly prognostic. Here we demonstrate that estrogen receptor-negative human breast cancer cell lines highly express Fra-1, c-Fos and c-Jun, components of the transcription factor, activator protein-1 (AP-1). Retrospective observation of breast cancer tissues obtained by core needle biopsy before surgery from stages II and III patients demonstrates that Fra-1 expression is high in estrogen receptor-negative human breast cancers, and negatively correlated to paclitaxel sensitivity. Ascochlorin, which suppresses cellular AP-1 activity, selectively kills estrogen receptor-negative human and mouse breast cancer cell lines, and prolongs the survival time of mice implanted with an estrogen receptor-negative mammary carcinoma. These results suggest that chemotherapy targeting AP-1 activity is a potent strategy for estrogen receptor-negative human breast cancers.

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Transcription factor decoy for AP-1 reduces mesangial cell proliferation and extracellular matrix production in vitro and in vivo

Cited by 47 publications

References 28 publications

Priming of Glomerular Mesangial Cells by Activated Macrophages Causes Blunted Responses to Proinflammatory Stimuli

Priming of Glomerular Mesangial Cells by Activated Macrophages Causes Blunted Responses to Proinflammatory Stimuli

Ring-Sp1 decoy oligonucleotide effectively suppresses extracellular matrix gene expression and fibrosis of rat kidney induced by unilateral ureteral obstruction

Aberrant Expression of Fra-1 in Estrogen Receptor-negative Breast Cancers and Suppression of their Propagation In Vivo by Ascochlorin, an Antibiotic that Inhibits Cellular Activator Protein-1 Activity

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