Inhibitory effect of anti-malarial agents on the expression of proinflammatory chemokines via Toll-like receptor 3 signaling in human glomerular endothelial cells

Background/Aims: Dysregulation of interleukin-6 (IL-6) production in residual renal cells may play a pivotal role in the development of glomerulonephritis (GN). Given that Toll-like receptor 3 (TLR3) signaling has been implicated in the pathogenesis of some forms of GN, we examined activated TLR3-mediated IL-6 signaling in cultured normal human glomerular endothelial cells (GECs). Methods: We treated GECs with polyinosinic-polycytidylic acid (poly IC), an authentic double-stranded RNA, and analyzed the expression of IL-6 and the cytosolic viral RNA sensors retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation associated gene 5 (MDA5) using reverse transcription quantitative real-time polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assays. To further elucidate the effects of poly IC on this signaling pathway, we subjected the cells to small interfering RNA (siRNA) against TLR3, interferon (IFN)-β, RIG-I, and MDA5. Results: We found that poly IC induced the expression of RIG-I, MDA5 and IL-6 via TLR3/IFN-β signaling in GECs. siRNA experiments revealed that both MDA5 and RIG-I were involved in the poly IC-induced expression of IL-6, with MDA5 being upstream of RIG-I. Conclusion: Interestingly, cytosolic sensors of viral RNA were found to be involved in IL-6 production via TLR3 signaling in GECs. Regional activation of TLR3/IFN-β/ MDA5/RIG-I/IL-6 axis due to viral and “pseudoviral” infections is involved in innate immunity and inflammatory reactions in GECs. We believe this signaling pathway also plays a pivotal role in the development of some forms of GN.

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Toll-like receptor 3 signaling and human glomerular endothelial cells

10.46439/nephrology.1.002 ◽

2020 ◽

Vol 1 (1) ◽

Keyword(s):

Endothelial Cells ◽

Toll Like Receptor ◽

Glomerular Endothelial Cells ◽

Human Glomerular Endothelial Cells

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IFIT Proteins Are Involved in CXCL10 Expression in Human Glomerular Endothelial Cells Treated with a Toll-Like Receptor 3 Agonist

Kidney & Blood Pressure Research ◽

10.1159/000511915 ◽

2020 ◽

pp. 1-12

Author(s):

Tadaatsu Imaizumi ◽

Shun Hashimoto ◽

Riko Sato ◽

Hidenori Umetsu ◽

Tomomi Aizawa ◽

...

Keyword(s):

Endothelial Cells ◽

Innate Immune ◽

Toll Like Receptor ◽

Tetratricopeptide Repeats ◽

Immune Reactions ◽

Polycytidylic Acid ◽

Glomerular Endothelial Cells ◽

Chemokine Ligand ◽

Human Glomerular Endothelial Cells ◽

Novel Coronavirus

Introduction: Various viruses including a novel coronavirus (SARS-CoV-2) can infect the kidney. When viruses invade the glomeruli from the bloodstream, glomerular endothelial cells (GECs) initiate the innate immune reactions. We investigated the expression of interferon (IFN)-induced protein with tetratricopeptide repeats (IFIT) 1/2/3, antiviral molecules, in human GECs treated with a toll-like receptor (TLR) 3 agonist. Role of IFIT1/2/3 in the expression of C-X-C motif chemokine ligand 10 (CXCL10) was also examined. Methods: Human GECs were cultured and stimulated with polyinosinic-polycytidylic acid (poly IC), a synthetic TLR3 agonist. Real-time qPCR, Western blotting, and ELISA were used to examine the expression of IFIT1/2/3, IFN-β, and CXCL10. RNA interference against IFN-β or IFIT1/2/3 was also performed. Results: Expression of IFIT1/2/3 and CXCL10 was induced by poly IC in GECs. The inductions were inhibited by RNA interfering of IFN-β. Knockdown of IFIT1/2/3 decreased the CXCL10 expression. Knockdown of IFIT3 decreased the expression of IFIT1 and IFIT2 proteins. Conclusion: IFIT1/2/3 and CXCL10 were induced by poly IC via IFN-β in GECs. IFIT1/2/3 may increase the expression of CXCL10 which induces lymphocyte chemotaxis and may inhibit the replication of infected viruses. These molecules may play a role in GEC innate immune reactions in response to viruses.

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Endothelial expression of fractalkine (CX3CL1) is induced by Toll-like receptor 3 signaling in cultured human glomerular endothelial cells

Modern Rheumatology ◽

10.1080/14397595.2019.1682768 ◽

2019 ◽

Vol 30 (6) ◽

pp. 1074-1081

Author(s):

Koji Hirono ◽

Tadaatsu Imaizumi ◽

Tomomi Aizawa ◽

Shojiro Watanabe ◽

Koji Tsugawa ◽

...

Keyword(s):

Endothelial Cells ◽

Toll Like Receptor ◽

Glomerular Endothelial Cells ◽

Human Glomerular Endothelial Cells

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Toll-Like Receptor 3 Signaling Contributes to Regional Neutrophil Recruitment in Cultured Human Glomerular Endothelial Cells

Nephron ◽

10.1159/000489507 ◽

2018 ◽

Vol 139 (4) ◽

pp. 349-358 ◽

Cited By ~ 4

Author(s):

Qiang Liu ◽

Tadaatsu Imaizumi ◽

Shogo Kawaguchi ◽

Tomomi Aizawa ◽

Tomoh Matsumiya ◽

...

Keyword(s):

Endothelial Cells ◽

Neutrophil Recruitment ◽

Toll Like Receptor ◽

Glomerular Endothelial Cells ◽

Human Glomerular Endothelial Cells

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Activation of general control nonderepressible 2 kinase protects human glomerular endothelial cells from harmful high-glucose-induced molecular pathways

International Urology and Nephrology ◽

10.1007/s11255-016-1377-x ◽

2016 ◽

Vol 48 (10) ◽

pp. 1731-1739 ◽

Cited By ~ 10

Author(s):

Theodoros Eleftheriadis ◽

Konstantina Tsogka ◽

Georgios Pissas ◽

Georgia Antoniadi ◽

Vassilios Liakopoulos ◽

...

Keyword(s):

Endothelial Cells ◽

High Glucose ◽

Molecular Pathways ◽

General Control ◽

Glomerular Endothelial Cells ◽

Human Glomerular Endothelial Cells

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Double-Stranded DNA Activates Glomerular Endothelial Cells and Enhances Albumin Permeability via a Toll-Like Receptor-Independent Cytosolic DNA Recognition Pathway

American Journal Of Pathology ◽

10.2353/ajpath.2009.090182 ◽

2009 ◽

Vol 175 (5) ◽

pp. 1896-1904 ◽

Cited By ~ 37

Author(s):

Holger Hägele ◽

Ramanjaneyulu Allam ◽

Rahul D. Pawar ◽

Christoph A. Reichel ◽

Fritz Krombach ◽

...

Keyword(s):

Endothelial Cells ◽

Dna Recognition ◽

Toll Like Receptor ◽

Double Stranded Dna ◽

Glomerular Endothelial Cells

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ATP stimulates Ca2+ mobilization by a nucleotide receptor in glomerular endothelial cells

AJP Renal Physiology ◽

10.1152/ajprenal.1994.266.2.f210 ◽

1994 ◽

Vol 266 (2) ◽

pp. F210-F217 ◽

Cited By ~ 5

Author(s):

V. A. Briner ◽

F. Kern

Keyword(s):

Endothelial Cells ◽

Receptor Agonist ◽

Rank Order ◽

P2y Receptors ◽

Inhibitory Effect ◽

P2x Receptor ◽

Dependent Manner ◽

Nucleotide Receptor ◽

Pyrimidine Nucleotide ◽

Glomerular Endothelial Cells

The present study investigates ATP effects on Ca2+ mobilization in bovine glomerular endothelial cells (GEC) and the receptors mediating ATP response. Extracellular ATP stimulated a rise in inositol 1,4,5-trisphosphate and cytosolic free Ca2+ concentration ([Ca2+]i) in a dose-dependent manner. Extracellular Ca2+ depletion did not prevent [Ca2+]i rise. ATP effects were not mediated by P1, P2x, and P2t purinoceptors, since the P1 receptor agonist adenosine and the P2x receptor agonist [alpha,beta-CH2]ATP had no effect on inositol 1-monophosphate (IP) formation and Ca2+ mobilization and ATP does not activate P2t receptors. The P2y receptor antagonist reactive blue (10(-3) M) had little inhibitory effect on ATP (10(-5) M)-stimulated IP formation (15.6 +/- 4.2%) and Ca2+ rise (7.0 +/- 3.0%). According to the classification of purinoceptors, ATP is less potent than 2-methylthioadenosine 5'-triphosphate (2-MeS-ATP) in stimulating P2y receptors. In GEC, however, the rank order of potency in stimulating IP and [Ca2+]i rise was ATP > 2-MeS-ATP > ADP. The pyrimidine nucleotide UTP (10(-3) M) induced maximal IP formation (653 +/- 37%) and Ca2+ mobilization (591 +/- 22 nM) similar to ATP (IP 647 +/- 27%; [Ca2+]i 583 +/- 15 nM). At submaximal (10(-5) M) but not at maximal (10(-3) M) doses ATP and UTP effects were additive. ATP and UTP induced specific cross-desensitization. It is concluded that the purinergic nucleotide ATP and pyrimidine nucleotide UTP mediate their effects by a common nucleotide receptor. This receptor differs from P2z and P2y1 receptors, since by definition UTP does not activate these receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

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