Toll-like receptor 3 ligands induce CD80 expression in human podocytes via an NF- B-dependent pathway

Shimada, Michiko; Ishimoto, Takuji; Lee, Pui Y.; Lanaspa, Miguel A.; Rivard, Christopher J.; Roncal-Jiménez, Carlos A.; Wymer, David T.; Yamabe, Hideaki; Mathieson, Peter W.; Saleem, Moin A.; Garin, Eduardo H.; Johnson, Richard J.

doi:10.1093/ndt/gfr271

Cited by 91 publications

(87 citation statements)

References 23 publications

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“…IFN family proteins have been implicated in the pathogenesis of focal segmental glomerulosclerosis, and TLR3 signaling in podocytes is thought to be involved in proteinuria [26]. Therefore, it is of interest to examine if TLR3 signaling regulates the expression of ISG56 in podocytes as well.…”

Section: Discussionmentioning

confidence: 99%

Interaction between Interferon-Stimulated Gene 56 and Melanoma Differentiation-Associated Gene 5 in Toll-Like Receptor 3 Signaling in Normal Human Mesangial Cells

Imaizumi¹,

Aizawa-Yashiro²,

Matsumiya³

et al. 2013

Am J Nephrol

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Background/Aims: Toll-like receptor 3 (TLR3) is a pathogen recognition receptor against viral double-stranded RNA. TLR3 signaling is important in antiviral responses, but inappropriate TLR3 signaling may be related with inflammatory renal diseases. Interferon (IFN)-stimulated gene 56 (ISG56) is an IFN-inducible gene that encodes a multifunctional protein with 6 tetratricopeptide motifs and is thought to be involved in antiviral reactions, but the role of ISG56 in TLR3 signaling in mesangial cells is not known well. Methods: Normal human mesangial cells were cultured and treated with a synthetic TLR3 ligand polyinosinic-polycytidylic acid, and the expression of ISG56 was analyzed using real-time RT-PCR and Western blot analyses. Using an RNA-interfering technique, involvement of TLR3, IFN-β, melanoma differentiation-associated gene 5 (MDA5) or retinoic acid-inducible gene-I (RIG-I) in ISG56 expression, and of ISG56 in the expression of MDA5, RIG-I, CXCL10 and CCL5 was examined. Results: Treatment of cells with polyinosinic-polycytidylic acid induced ISG56. ISG56 induction was inhibited by knockdown of TLR3 or IFN-β, and knockdown of ISG56 resulted in the decreased expression of MDA5, RIG-I, CXCL10 and CCL5. RNA interference against MDA5 decreased ISG56 expression. Conclusion: ISG56 was induced by TLR3 signaling via newly synthesized IFN-β. ISG56 is involved in the expression of MDA5, RIG-I, CXCL10 and CCL5, and ISG56 and MDA5 may constitute a positive-feedback loop. ISG56 may play a role in immune and inflammatory reactions induced by TLR3 signaling in human mesangial cells.

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Section: Discussionmentioning

confidence: 99%

Interaction between Interferon-Stimulated Gene 56 and Melanoma Differentiation-Associated Gene 5 in Toll-Like Receptor 3 Signaling in Normal Human Mesangial Cells

Imaizumi¹,

Aizawa-Yashiro²,

Matsumiya³

et al. 2013

Am J Nephrol

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“…Recent observations have revealed that NF-κB of podocyte and peripheral blood mononuclear cells (PBMC) play an important role in the development of proteinuria in MCNS because it regulates cytokine expression, through association with other transcription factors and protein-protein interactions with coactivator proteins [5]: e.g., Shimada et al [18] reported that an activation of Toll-like receptor 3 on cultured human podocytes induces CD80 expression and phenotypic change via an NF-κB-dependent mechanism and is partially blocked by dexamethasone; Cao et al [19] postulated that the abnormal activation of NF-κB is involved in the pathogenesis of MCNS providing that its DNA-binding abilities were significantly increased in PBMC from MCNS patients compared with controls, and there were strong correlations between urinary protein and the baseline DNA-binding ability of NF-κB; Sahali et al [20] demonstrated that nuclear extracts from PBMC during relapse in patients with MCNS displayed high levels of NF-κB DNA-binding activity.…”

Section: Discussionmentioning

confidence: 99%

A Novel Nuclear Factor κB Inhibitor, Dehydroxymethylepoxyquinomicin, Ameliorates Puromycin Aminonucleoside-Induced Nephrosis in Mice

et al. 2013

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Background/Aims: Minimal-change nephrotic syndrome (MCNS) is a kidney disease defined by selective proteinuria and hypoalbuminemia occurring in the absence of cellular glomerular infiltrates or immunoglobulin deposits. Recent observations suggest that nuclear factor κB (NF-κB) of podocyte is strongly associated with the development of proteinuria in MCNS. Dehydroxymethylepoxyquinomicin (DHMEQ) is a novel NF-κB inhibitor that potently inhibits DNA-binding activity of NF-κB, resulting in several therapeutic effects in various pathological conditions. We conducted this study to ask whether DHMEQ may ameliorate the nephrosis in mice induced by puromycin aminonucleoside (PAN), which is considered to be an animal model for MCNS. Methods/Results: Pretreatment with DHMEQ alleviated the proteinuria and reversed the serum abnormalities in mice nephrosis induced by 450 mg/kg of PAN. Increased serum interleukin-6 level in PAN-induced nephrosis was also completely suppressed by DHMEQ. Electron microscopic analyses of glo-meruli indicated that DHMEQ can inhibit the podocyte foot process effacement via blocking the translocation of podocyte NF-κB from cytoplasm to nucleus. Conclusions: These results suggest that DHMEQ can be a potential therapeutic agent for MCNS.

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“…CD80 is also present in the podocytes of mice in MCD models and is necessary for resulting proteinuria. [7][8][9] Soluble urinary CD80 levels are elevated in children and adolescents with MCD in relapse compared with those individuals in remission, patients with other glomerular disease, and control subjects. 10 Furthermore, urinary CD80/creatinine ratios are increased in MCD in relapse compared with MCD in remission or FSGS.…”

Section: Pathophysiologymentioning

confidence: 99%

The Treatment of Minimal Change Disease in Adults

Hogan

Radhakrishnan

2013

Journal of the American Society of Nephrology

128

123

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Minimal change disease (MCD) is the etiology of 10%-25% of cases of nephrotic syndrome in adults. The mainstay of treatment for adult MCD, oral gucocorticoids, is based on two randomized controlled trials and extensive observational data in adults, and this treatment leads to remission in over 80% of cases. Relapses are common, and some patients become steroid-resistant (SR), steroid-dependent (SD), or frequently relapsing (FR). The data guiding the treatment of these patients are limited. Here, we review MCD in adults with particular focus on the evidence for immunosuppressive therapy in these patients.

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Toll-like receptor 3 ligands induce CD80 expression in human podocytes via an NF- B-dependent pathway

Abstract: Activation of TLR3 on cultured human podocytes induces CD80 expression and phenotypic change via an NF-κB-dependent mechanism and is partially blocked by dexamethasone. These studies provide a mechanism by which viral infections may cause proteinuria.

Cited by 91 publications

References 23 publications

Interaction between Interferon-Stimulated Gene 56 and Melanoma Differentiation-Associated Gene 5 in Toll-Like Receptor 3 Signaling in Normal Human Mesangial Cells

Interaction between Interferon-Stimulated Gene 56 and Melanoma Differentiation-Associated Gene 5 in Toll-Like Receptor 3 Signaling in Normal Human Mesangial Cells

A Novel Nuclear Factor κB Inhibitor, Dehydroxymethylepoxyquinomicin, Ameliorates Puromycin Aminonucleoside-Induced Nephrosis in Mice

The Treatment of Minimal Change Disease in Adults

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Toll-like receptor 3 ligands induce CD80 expression in human podocytes via an NF- B-dependent pathway

Abstract: Activation of TLR3 on cultured human podocytes induces CD80 expression and phenotypic change via an NF-κB-dependent mechanism and is partially blocked by dexamethasone. These studies provide a mechanism by which viral infections may cause proteinuria.

Cited by 91 publications

References 23 publications

Interaction between Interferon-Stimulated Gene 56 and Melanoma Differentiation-Associated Gene 5 in Toll-Like Receptor 3 Signaling in Normal Human Mesangial Cells

Interaction between Interferon-Stimulated Gene 56 and Melanoma Differentiation-Associated Gene 5 in Toll-Like Receptor 3 Signaling in Normal Human Mesangial Cells

A Novel Nuclear Factor &#954;B Inhibitor, Dehydroxymethylepoxyquinomicin, Ameliorates Puromycin Aminonucleoside-Induced Nephrosis in Mice

The Treatment of Minimal Change Disease in Adults

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Resources

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A Novel Nuclear Factor κB Inhibitor, Dehydroxymethylepoxyquinomicin, Ameliorates Puromycin Aminonucleoside-Induced Nephrosis in Mice