| 1.
論文 |
論文
|
Harada, Nobuhiko ; Matsuura, Shin ; Kanayama, Masaya ; Yoshida, Aruto ; Itoh, Ken
概要:
The long-term function of a graft after transplantation is dependent upon ischemia-reperfusion （I/R） injury, which repre
…
sents the most important alloantigen-independent damage processes during transplantation. Basic leucine zipper（ b-Zip） transcription factor NF-E2-related factor 2（ Nrf2） is protective against I/R injury by promoting antioxidative and anti-inflammatory mechanisms via up-regulation of antioxidant-responsive element （ARE）-regulated genes such as heme oxygenase 1 and γ-glutamylcysteine ligase. We previously demonstrated that macrophage Nrf2 plays an important role in an elastase-induced acute lung injury model. To further clarify the mechanisms that act downstream of Nrf2, we performed microarray analysis in the RAW264.7 murine macrophage cell line using endogenous electrophilic prostaglandin 15-deoxy-Δ12,14-prostagrandin J2 （15d-PGJ2）. As a result, we identified ferroportin 1 （Fpn1） as a novel Nrf2 target gene. Fpn1 is the sole iron exporter in mammals and regulates iron homeostasis. On the other hand, free intracellular iron is detrimental to cells by enhancing both inflammation and Fenton reaction-mediated oxidative stress. We demonstrated that Nrf2 activation by several electrophilic compounds commonly result in the up-regulation of Fpn1 mRNA in bone marrow-derived and peritoneal macrophages obtained from wild-type, but not from Nrf2 knockout mice. Furthermore, Nrf2 activation enhances iron release from the murine macrophage cell line J774.1. It is previously reported that LPS suppresses Fpn1 mRNA expression, which leads to iron retention in monocytes and macrophages. We showed that while LPS suppress Fpn1 mRNA expression in human macrophages, Nrf2 activation restores the expression of Fpn1. Thus, we propose that iron-metabolism regulation may be an important factor of the Nrf2-mediated cytoprotectivemechanism.
続きを見る
|
||||
| 2.
論文 |
論文
|
Imaizumi, Tadaatsu ; Hayakari, Ryo ; Watanabe, Shojiro ; Aizawa, Tomomi ; Matsumiya, Tomoh ; Yoshida, Hidemi ; Tsuruga, Kazushi ; Kawaguchi, Shogo ; Tanaka, Hiroshi
概要:
Cylindromatosis (CYLD), a deubiquitinase, negatively regulates nuclear factor-κB in various cells. However, its potentia
…
l roles in glomerular inflammation remain unclear. Because the activation of the Toll-like receptor 3 (TLR3)/type I interferon (IFN) pathways plays a pivotal role in chronic kidney diseases (CKD), we examined the role of CYLD in the TLR3 signaling in cultured human mesangial cells (MCs).<br />We stimulated CYLD-silenced MCs with polyinosinic-polycytidylic acid (poly IC), a synthetic analogue of dsRNA, and studied representative TLR3/IFN-β pathways (i.e., TLR3/IFN-β/retinoic acid-inducible gene-I (RIG-I)/CCL5, and TLR3/IFN-β/melanoma differentiation associated gene 5 (MDA5)/CXCL10 axes) using RT-PCR, western blotting, and ELISA. We also used immunofluorescence staining and microscopy to examine mesangial CYLD expression in biopsied specimens from patients with CKD.<br />CYLD silencing resulted in an increase of poly IC-induced RIG-I and MDA5 protein levels and increased CCL5 and CXCL10 mRNA and protein expression, but unexpectedly decreased mRNA expressions of RIG-I and MDA5. Interestingly, CYLD silencing did not affect IFN-β or the phosphorylated STAT1 (signal transducers and activator of transcription protein 1). CYLD was highly expressed in biopsied specimens from patients with proliferative lupus nephritis (LN).<br />CYLD inhibits post-transcriptional regulation of RIG-I and MDA5 expression following TLR3 activation in MCs. CYLD may be involved in the pathogenesis of CKD, especially pathogenesis of LN.
続きを見る
|
||||
| 3.
論文 |
論文
|
Imaizumi, Tadaatsu ; Yano, Chikashi ; Numata, Akiko ; Tsugawa, Koji ; Hayakari, Ryo ; Matsumiya, Tomoh ; Yoshida, Hidemi ; Watanabe, Shojiro ; Tsuruga, Kazushi ; Kawaguchi, Shogo ; Murakami, Manabu ; Tanaka, Hiroshi
概要:
Activation of Toll-like receptor 3 (TLR3) signaling followed by type I interferon (IFN) expression is crucial in antivir
…
al and "pseudoviral" immune reactions in renal mesangial cells (MCs). These reactions are probably involved in the pathogenesis of chronic kidney disease (CKD). However, the role of IFN-induced 35-kDa protein 35 (IFI35), a type I IFN-dependent transcript, in glomerular inflammation is unclear. Here, we aimed to investigate the expression and the role of IFI35 in IFN-β/retinoic acid-inducible gene-I (RIG-I)/CCL5 and IFN-β/melanoma differentiation-associated gene 5 (MDA5)/CXCL10 axes in MCs.<br />We treated human MCs with polyinosinic-polycytidylic acid (poly IC), an authentic double-stranded RNA, then analysed the IFI35 expression by reverse transcription-polymerase chain reaction and western blotting. To examine the regulation of IFI35 expression, we subjected MCs to RNA interference (siRNA) against IFN-β, RIG-I, and MDA5.<br />Activation of TLR3 by poly IC induces the IFI35 expression in MCs. siRNA against IFN-β inhibited poly IC-induced IFI35 expression. Knockdown of IFI35 resulted in a decrease of poly IC-induced RIG-I and MDA5 protein as well as decreased CCL5 and CXCL10 mRNA and protein expression. However, it did not affect the expression of none of phosphorylated signal transducers or activator of transcription (STAT) 1 protein, or RIG-I and MDA5 in mRNA levels.<br />Regional expression of IFI35 and its dysregulation may be involved in the pathogenesis of glomerular inflammation in CKD.
続きを見る
|
||||
| 4.
論文 |
論文
|
Aizawa, Tomomi ; Imaizumi, Tadaatsu ; Tsuruga, Kazushi ; Watanabe, Shojiro ; Yoshida, Hidemi ; Kumagai, Naonori ; Ito, Etsuro ; Tanaka, Hiroshi
概要:
Renal biopsy is the gold standard for confirmation of disease severity and diagnosis of glomerulonephritis (GN), but its procedure is invasive with a risk of complications. Thus, a non-invasive monitoring method is desirable especially
…
in pediatric patients. Fractalkine and monocyte chemoattractant protein-1 (MCP-1) are proinflammatory chemokines, and both have been reported to be involved in the pathogenesis of immunocomplex-mediated GN. Recently, it has been reported that urinary fractalkine and MCP-1 may serve as possible predictors of disease activity of adult patients with GN. We, therefore, examined whether urinary levels of fractalkine and MCP-1 correlate with clinical and histologic parameters. Twenty-six consecutive children with various types of GN were enrolled in this study, including lupus nephritis, IgA nephropathy, membranous nephropathy, acute GN, and thin basement membrane disease (served as a non-inflammatory control). Urinary fractalkine and MCP-1 concentrations in the first morning urine samples obtained at the time of renal biopsy were measured by enzyme-linked immunosorbent assay, and standardized for urinary creatinine concentrations. Urinary fractalkine concentration differed significantly among the disease categories. Urinary concentrations of fractalkine and MCP-1 showed a significant positive correlation with the degree of occult blood in urine and a significant inverse correlation with the estimated glomerular filtration rate. Furthermore, the urinary MCP-1 concentration was significantly correlated with histological chronicity indices in patients with lupus nephritis and IgA nephropathy. Measurement of urinary fractalkine and MCP-1 concentrations may be useful as a non-invasive method for predicting the disease activity of GN in children.
続きを見る
|
