Gadolinium compounds signaling through TLR4 and TLR7 in normal human macrophages: establishment of a proinflammatory phenotype and implications for the pathogenesis of nephrogenic systemic fibrosis.
Nephrogenic systemic sibrosis is a progressive disorder occurring in some renal insufficiency patients exposed to gadolinium-based contrast agents (GdBCA). Previous studies demonstrated that the GdBCA Omniscan upregulated several innate immunity pathways in normal differentiated human macrophages, induced rapid nuclear localization of the transcription factor NF-κB, and increased the expression and production of numerous profibrotic/proinflammatory cytokines, chemokines, and growth factors. To further examine GdBCA stimulation of the innate immune system, cultured human embryonic kidney 293 cells expressing one of seven different human TLRs or one of two human nucleotide-binding oligomerization domain-like receptors were exposed in vitro for 24 h to various GdBCA. The signaling activity of each compound was evaluated by its ability to activate an NF-κB-inducible reporter gene. Omniscan and gadodiamide induced strong TLR4- and TLR7-mediated reporter gene activation. The other Gd compounds examined failed to induce reporter gene activation. TLR pathway inhibition using chloroquine or an inhibitor of IL-1R-associated kinases 1 and 4 in normal differentiated human macrophages abrogated Omniscan-induced gene expression. Omniscan and gadodiamide signaling via TLRs 4 and 7 resulted in increased production and expression of numerous proinflammatory/profibrotic cytokines, chemokines, and growth factors, including CXCL10, CCL2, CCL8, CXCL12, IL-4, IL-6, TGF-β, and vascular endothelial growth factor. These observations suggest that TLR activation by environmental stimuli may participate in the pathogenesis of nephrogenic systemic fibrosis and of other fibrotic disorders including systemic sclerosis.
Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Peter J
PJ
Wermuth
Sergio A
SA
Jimenez
D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D003287:Contrast Media / Q000009:adverse effects; D005682:Gadolinium / Q000009:adverse effects* / Q000502:physiology; D019786:Gadolinium DTPA / Q000009:adverse effects; D057809:HEK293 Cells; D006801:Humans; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000009:adverse effects* / Q000502:physiology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D054989:Nephrogenic Fibrosing Dermopathy / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D034622:RNA Interference / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000502:physiology*; D051199:Toll-Like Receptor 7 / Q000037:antagonists & inhibitors / Q000502:physiology*
D003287:Contrast Media; D018836:Inflammation Mediators; C495345:TLR4 protein, human; C495348:TLR7 protein, human; D051197:Toll-Like Receptor 4; D051199:Toll-Like Receptor 7; C064925:gadodiamide; D005682:Gadolinium; D019786:Gadolinium DTPA