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Novel role of toll-like receptor 3 in hepatitis C-associated glomerulonephritis.

ABSTRACT: Hepatitis C virus (HCV) infection is frequently complicated by glomerulonephritis with immune complexes containing viral RNA. We examined the potential influence of Toll-like receptors (TLRs), specifically TLR3 recognition of viral dsRNA exemplified by polyriboinosinic:polyribocytidylic acid [poly(I:C) RNA]. Normal human kidney stained positive for TLR3 on mesangial cells (MCs), vascular smooth muscle cells, and collecting duct epithelium. Cultured MCs have low TLR3 mRNA levels with predominant intracellular protein localization, which was increased by tumor necrosis factor-alpha, interleukin (IL)-1beta, interferon (IFN)-gamma, and the TLR3 ligand poly(I:C) RNA. Poly(I:C) RNA stimulation of MCs increased mRNA and protein synthesis of IL-6, IL-1beta, M-CSF, IL-8/CXCL8, RANTES/CCL5, MCP-1/CCL2, and ICAM-I; it also increased anti-proliferative and proapoptotic effects, the latter of which was decreased by inhibiting caspase-8. In microdissected glomeruli of normal and non-HCV membranoproliferative glomerulonephritis biopsies, TLR3 mRNA expression was low. In contrast TLR3 mRNA expression was significantly increased in hepatitis C-positive glomerulonephritis and was associated with enhanced mRNA for RANTES/CCL5 and MCP-1/CCL2. We hypothesize that immune complexes containing viral RNA activate mesangial TLR3 during HCV infection, thereby contributing to chemokine/cytokine release and effecting proliferation and apoptosis. Thus, TLR3 expression on renal cells, and especially MCs, may establish a link between viral infections and glomerular diseases.

SUBMITTER: Wornle M

PROVIDER: S-EPMC1606499 | biostudies-literature | 2006 Feb

REPOSITORIES: biostudies-literature

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Novel role of toll-like receptor 3 in hepatitis C-associated glomerulonephritis.

Wörnle Markus M Schmid Holger H Banas Bernhard B Merkle Monika M Henger Anna A Roeder Maximilian M Blattner Simone S Bock Elisabeth E Kretzler Matthias M Gröne Hermann-Josef HJ Schlöndorff Detlef D

The American journal of pathology 20060201 2

Hepatitis C virus (HCV) infection is frequently complicated by glomerulonephritis with immune complexes containing viral RNA. We examined the potential influence of Toll-like receptors (TLRs), specifically TLR3 recognition of viral dsRNA exemplified by polyriboinosinic:polyribocytidylic acid [poly(I:C) RNA]. Normal human kidney stained positive for TLR3 on mesangial cells (MCs), vascular smooth muscle cells, and collecting duct epithelium. Cultured MCs have low TLR3 mRNA levels with predominant ...[more]

PMID: 16436653

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Project description:Tumour necrosis factor alpha (TNF?) is a cytokine that is pivotal in the inflammatory response. Blockade of TNF? has been shown to be effective in a number of human autoimmune diseases, including rheumatoid arthritis, raising the question of whether this approach may be effective in inflammatory kidney disease, such as ANCA-associated vasculitis (AAV). In AAV, there is considerable evidence for the role of TNF? in the pathophysiology of disease, including increased expression of TNF? mRNA in leucocytes and in renal tissue. Importantly, TNF? can induce leucocyte cell membrane expression of the autoantigens involved in vasculitis [proteinase 3 and myeloperoxidase (MPO)], thus priming cells for the effects of ANCA. In rodent models of anti-GBM disease (nephrotoxic nephritis), TNF? enhances glomerular injury and TNF? blockade using soluble TNF? receptor or anti-TNF? antibody ameliorates disease. Mice deficient in TNF? are protected from nephrotoxic nephritis and this effect is dependent mainly on intrinsic renal cells. A mouse model of anti-MPO antibody-induced glomerulonephritis is enhanced by LPS, and this effect is blocked by anti-TNF? antibody. In a rat model of AAV induced by MPO (experimental autoimmune vasculitis), anti-TNF? antibody improves renal pathology and also reduces leucocyte transmigration, as shown by intravital microscopy. In clinical studies, the Wegener's Granulomatosis Etanercept Trial (WGET) showed no benefit of additional etanercept versus standard therapy. However, there are several reasons why the results of the WGET study do not rule out the use of anti-TNF? antibody in acute renal AAV, including the study design and the considerable biological differences between the effects of etanercept and anti-TNF? antibody. There are several clinical studies demonstrating a response to anti-TNF? antibody in patients with AAV refractory to conventional treatment, and in some of these, the addition of anti-TNF? antibody was the only change in treatment. We suggest that further investigation of TNF? blockade in AAV is warranted.

Dataset Information

Novel role of toll-like receptor 3 in hepatitis C-associated glomerulonephritis.

Publications

Novel role of toll-like receptor 3 in hepatitis C-associated glomerulonephritis.

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