Gd compounds signaling through Toll-like receptors 4 and 7 in normal human macrophages: establishment of a proinflammatory phenotype and implications for the pathogenesis of Nephrogenic Systemic Fibrosis

摘要

Nephrogenic Systemic Fibrosis (NSF) is a progressive disorder occurring in some renal insufficiency patients exposed to Gd 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 NFκB, 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 (HEK293) cells expressing one of seven different human TLRs or one of two human Nucleotide Oligomerization Domain (NOD)-like receptors (NLRs) were exposed in vitro for 24 h to various GdBCA. The signaling activity of each compound was evaluated by its ability to activate an NFκB-inducible reporter gene. Omniscan^® and gadodiamide induced strong TLR 4 and 7 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-1 receptor associated kinase 1 (IRAK1) and IRAK4 in normal differentiated human macrophages abrogated Omniscan^®-induced gene expression. Omniscan^® and gadodiamide signaling via TLR 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 VEGF. These observations suggest that TLR activation by environmental stimuli may participate in the pathogenesis of NSF and of other fibrotic disorders including systemic sclerosis.