Melanoma Differentiation-Associated Gene 5 Regulates the Expression of a Chemokine CXCL10 in Human Mesangial Cells: Implications for Chronic Inflammatory Renal Diseases

Imaizumi, Tadaatsu; Aizawa-Yashiro, Tomomi; Tsuruga, Kazushi; Tanaka, Hiroshi; Matsumiya, Tomoh; Yoshida, Hidemi; Tatsuta, Tetsuya; Xing, Fei; Hayakari, Ryo; Satoh, Kei

doi:10.1620/tjem.228.17

Cited by 37 publications

(61 citation statements)

References 25 publications

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“…In this present study, we introduced poly(I:C) into cells to test for a role of RLR signaling. We previously showed that the application of dsRNA to cells is sensed by TLRs, whereas transfected dsRNA can activate RLR signaling [26]. Our data showed that both HBEpCs and HPAEpiCs have an intact RLR signaling pathway.…”

Section: Discussionmentioning

confidence: 53%

Retinoic acid-inducible gene-I-like receptor (RLR)-mediated antiviral innate immune responses in the lower respiratory tract: Roles of TRAF3 and TRAF5

Chiba

Matsumiya

Satoh

et al. 2015

Biochemical and Biophysical Research Communications

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Upon viral infection, the cytoplasmic viral sensor retinoic acid-inducible gene-I (RIG-I) recognizes viral RNA to activate antiviral signaling to induce type I interferon (IFN).RIG-I-like receptors (RLRs) activate antiviral signaling in a tissue-specific manner. The molecular mechanism underlying antiviral signaling in the respiratory system remains unclear.We studied antiviral signaling in the lower respiratory tract (LRT), which is the site of many harmful viral infections. Epithelial cells of the LRT can be roughly divided into two groups: bronchial epithelial cells (BECs) and pulmonary alveolar epithelial cells (AECs). These two cell types exhibit different phenotypes; therefore, we hypothesized that these cells may play different roles in antiviral innate immunity. We found that BECs exhibited higher antiviral activity than AECs. TNF receptor-associated factor 3 (TRAF3) has been shown to be a crucial molecule in RLR signaling. The expression levels of TRAF3 and TRAF5, which have conserved domains that are nearly identical, in the LRT were examined. We found that the bronchus exhibited the highest expression levels of TRAF3 and TRAF5 in the LRT. These findings suggest the importance of the bronchus in antiviral innate immunity in the LRT and indicate that TRAF3 and TRAF5 may contribute to RLR signaling.

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Section: Discussionmentioning

confidence: 53%

Retinoic acid-inducible gene-I-like receptor (RLR)-mediated antiviral innate immune responses in the lower respiratory tract: Roles of TRAF3 and TRAF5

Chiba

Matsumiya

Satoh

et al. 2015

Biochemical and Biophysical Research Communications

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“…Knockdown of DEC1 enhanced the poly IC-induced expression of proteins for CXCL10, CCL5, MDA5 and RIG-I, and mRNAs for CXCL10 and CCL5. CXCL10 is a chemokine that promotes the chemotaxis of lymphocytes, and is implicated in the pathogenesis of glomerular nephritis including lupus nephritis and IgA nephropathy (13). CCL5 is a chemokine that is chemotactic for leukocytes such as T-cells and eosinophils (9).…”

Section: Discussionmentioning

confidence: 99%

“…We previously reported that poly IC activates the TLR3/IFN-β/MDA5/CXCL10 and TLR3/IFN-β/ RIG-I/CCL5 axes in human mesangial cells (13,16). To examine whether DEC1 is involved in these axes, the cells were transiently transfected with siRNA against DEC1.…”

Section: Effect Of Knockdown Of Dec1 On Poly Ic-induced Expression Ofmentioning

confidence: 99%

“…This suggests that constitutively expressed DEC1 may exert the inhibitory effect on innate immune reactions. High levels of MDA5 and RIG-I have been observed in renal biopsy specimens from patients with proliferative lupus nephritis, and MDA5 immunoreactivity was observed in biopsy specimens from patients with proteinuric IgA nephropathy (13,27). MDA5 and RIG-I are members of ISGs.…”

Section: Effect Of Knockdown Of Dec1 On Poly Ic-induced Expression Ofmentioning

confidence: 99%

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<b>DEC1 negatively regulates the expression of CXCL10 and CCL5 induced by poly IC in normal human mesangial </b><b>cells </b>

et al. 2017

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The functions of differentiated embryonic chondrocyte gene (DEC) 1, a basic helix-loop-helix (bHLH) transcription factor, have been reported to be associated with the regulation of mammalian circadian rhythms, differentiation of chondrocytes and skeletal muscles, apoptosis, hypoxiainduced reactions and epithelial mesenchymal transition. Our previous report showed that another bHLH transcription factor DEC2 constitutes a negative feedback loop in Toll-like receptor 3 (TLR3)/interferon (IFN)-β-mediated inflammatory responses in human mesangial cells. However, the role of DEC1 in innate immune responses remains unclear. We have previously reported TLR3/IFN-β/retinoic acid-inducible gene-I (RIG-I)/CCL5 and TLR3/IFN-β/melanoma differentiation-associated gene 5 (MDA5)/CXCL10 axes in cultured normal human mesangial cells treated with polyinosinic-polycytidylic acid (poly IC), a synthetic double-stranded RNA that is sensed by TLR3. The present study was carried out to examine the involvement of DEC1 in these axes. DEC1 was constitutively expressed in human mesangial cells, and the expression was not altered by treatment with poly IC. Interestingly, RNA interference against DEC1 markedly enhanced the poly IC-induced expression of chemokines CXCL10 and CCL5. Knockdown of DEC1 increased the poly IC-induced MDA5 and RIG-I protein expression without affecting mRNA expression, and did not affect phosphorylation of signal transducer and transcription 1 (STAT1). DEC1 may serve as an anti-inflammatory factor by negative regulation of MDA5/CXCL10 and RIG-I/CCL5 in human mesangial cells treated with poly IC.Differentiated embryonic chondrocyte gene (DEC) 1, also known as BHLHE40, SHARP2 or Stra13, belongs to a superfamily of basic helix-loop-helix (bHLH) transcription factors, and binds to E-box elements in the promoters and/or enhancer regions of the target genes. DEC1 has been reported to be associated with the regulation of mammalian circadian rhythms, differentiation of chondrocytes and skeletal muscles, apoptosis, hypoxia-induced responses as well as epithelial mesenchymal transition (EMT) (1,10, 25, 28, 34, 35). An initial study on DEC1-deficient mice demonstrated that DEC1 is essential for T cell activation-induced cell death. Indeed, DEC1 deficiency in mice have defective T cell-mediated recall responses, causing lymphoid organ hyperplasia and systemic autoimmune disease (30). Another report showed that DEC1 is overexpressed in human chronic gingivitis and chronic

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“…It has been reported that TLR3 signalling in human glomerular mesangial cells induces chemokine ligand 5 (CCL5) and C-X-C motif chemokine 10 (CXCL10) via the TLR3-interferon-β (IFN-β)-retinoic acid-inducible gene-I (RIG-I)-CCL5 [21] and TLR3-IFN-β-melanoma differentiation-associated protein 5 (MDA5)-CXCL10 axes [22], respectively.…”

Section: Discussionmentioning

confidence: 99%

A Functional Polymorphism in the Promoter Region of TLR3 Is Associated with Susceptibility to End-Stage Renal Disease

Yang

Huang

et al. 2014

Am J Nephrol

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Background/Aims: End-stage renal disease (ESRD) is simultaneously associated with immune activation, systemic inflammation and immune deficiency. Toll-like receptor 3 (TLR3), a receptor for viral double-stranded RNA, is involved in immune cell activation in renal diseases and may contribute to chronic inflammatory disease progression. To date, effects of TLR3 polymorphisms on ESRD remain unknown. Therefore, we determined the predictive value of TLR3 polymorphisms and further functionally studied ESRD. Methods: We performed a case-control association study and genotyped 616 ESRD patients and 813 healthy controls. Patients were genotyped for -7C/A, 1377C/T and 1234C/T polymorphisms of TLR3 using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. The Haplotype association analysis was performed using the Haploview package. A luciferase reporter assay and real-time PCR were used to test the function of the -7C/A promoter polymorphism in TLR3 expression in human embryonic kidney 293 (HEK293) cells. Results: Genotype distributions of -7C/A and 1377C/T in TLR3 were significantly different in ESRD patients and healthy controls. The ATC haplotype of TLR3 was associated with a decreased risk of ESRD. We also found significant differences in TLR3 expression by dexamethasone treatment between various genotypes of -7C/A (p = 0.02). TLR3 transcriptional activity of the variant -7 C allele was higher than that of the -7 A allele after dexamethasone treatment. Conclusion: Results indicate that, in our population, the presence of the C allele of -7C/A in TLR3 increases the susceptibility to ESRD. In vitro studies demonstrated that -7C/A may be involved in ESRD development through transcriptional modulation of TLR3.

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Melanoma Differentiation-Associated Gene 5 Regulates the Expression of a Chemokine CXCL10 in Human Mesangial Cells: Implications for Chronic Inflammatory Renal Diseases

Cited by 37 publications

References 25 publications

Retinoic acid-inducible gene-I-like receptor (RLR)-mediated antiviral innate immune responses in the lower respiratory tract: Roles of TRAF3 and TRAF5

Retinoic acid-inducible gene-I-like receptor (RLR)-mediated antiviral innate immune responses in the lower respiratory tract: Roles of TRAF3 and TRAF5

<b>DEC1 negatively regulates the expression of CXCL10 and CCL5 induced by poly IC in normal human mesangial </b><b>cells </b>

A Functional Polymorphism in the Promoter Region of TLR3 Is Associated with Susceptibility to End-Stage Renal Disease

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