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Viral rna induces type i interferon-dependent cytokine release and cell death in mesangial cells via melanoma-differentiation-associated gene-5 implications for viral infection-associated glomerulonephritis

Academic Article
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Overview

authors

  • Flur, K.
  • Allam, R.
  • Zecher, D.
  • Kulkarni, O. P.
  • Lichtnekert, J.
  • Schwarz, M.
  • Beutler, Bruce
  • Vielhauer, V.
  • Anders, H. J.

publication date

  • November 2009

journal

  • American Journal of Pathology  Journal

abstract

  • Viral RNA can trigger interferon signaling in dendritic cells via the innate recognition receptors melanoma-differentiation-associated gene (MDA)-5 and retinod-inducible gene (RIG)-I in the cytosol or via Toll-like receptors (TLRs) in intracellular endosomes. We hypothesized that viral RNA would also activate glomerular mesangial cells to produce type I interferon (IFN) via TLR-dependent and TLR-independent pathways. To test this hypothesis, we examined Toll/Interleukin-1 receptor domain-containing adaptor-inducing interferon-beta (TRIF)-deficient mice, which lack a key adaptor for TLR3 signaling. In primary mesangial cells, poly I:C RNA-mediated IFN-beta induction was partially TRIF dependent; however, when poly I:C RNA was complexed with cationic lipids to enhance cytosolic uptake, mesangial cells produced large amounts of IFN-alpha and IFN-beta independent of TRIF. Mesangial cells expressed RIG-I and MDA-5 and their mitochondrial adaptor IFN-beta promoter stimulator-1 as well, and small interfering RNA studies revealed that MDA5 but not RIG-I was required for cytosolic poly I:C RNA signaling. In addition, mesangial cells produced Il-6 on stimulation with IFN-alpha and IFN-beta, suggesting an autocrine proinflammatory effect. Indeed, blockade of IFN-alphabeta or lack of the IFNA receptor reduced viral RNA-induced Il-6 production and apoptotic cell death in mesangial cells. Furthermore, viral RNA/cationic lipid complexes increased focal necrosis in murine nephrotoxic serum nephritis in association with increased renal mRNA expression of IFN-related genes. Thus, TLR-independent recognition of viral RNA is a potent inducer of type I interferon in mesangial cells, which can be an important mediator of virally induced glomerulonephritis.

subject areas

  • Animals
  • Cell Death
  • Cytokines
  • DEAD-box RNA Helicases
  • Female
  • Glomerulonephritis
  • Interferon Type I
  • Kidney Glomerulus
  • Membrane Proteins
  • Mesangial Cells
  • Mice
  • Mice, Inbred C57BL
  • Nephritis
  • Nerve Tissue Proteins
  • Poly I-C
  • RNA, Small Interfering
  • RNA, Viral
  • Toll-Like Receptors
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Identity

PubMed Central ID

  • PMC2774065

International Standard Serial Number (ISSN)

  • 0002-9440

Digital Object Identifier (DOI)

  • 10.2353/ajpath.2009.080585

PubMed ID

  • 19850889
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Additional Document Info

start page

  • 2014

end page

  • 2022

volume

  • 175

issue

  • 5

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