Induction of a type I interferon signature in normal human monocytes by gadolinium-based contrast agents: comparison of linear and macrocyclic agents

Abstract

SummaryThe gadolinium-based contrast agent (GdBCA) Omniscan activates human macrophages through Toll-like receptor (TLR)-4 and TLR-7 signalling. To explore the mechanisms responsible we compared the ability of linear and macrocyclic GdBCA to induce a type I interferon signature and a proinflammatory/profibrotic phenotype in normal human monocytes in vitro. Expression of genes associated with type I interferon signalling and inflammation and production of their corresponding proteins were determined. Both linear and macrocyclic GdBCA stimulated expression of multiple type I interferon-regulated genes and the expression of numerous chemokines, cytokines and growth factors in normal human peripheral blood monocytes. There was no correlation between the magnitude of the measured response and the Gd chelate used. To explore the mechanisms responsible for GdBCA induction of fibrosis in nephrogenic systemic fibrosis (NSF) in vitro, normal human dermal fibroblasts were incubated with GdBCA-treated monocyte culture supernatants and the effects on profibrotic gene expression were examined. Supernatants from monocytes exposed to all GdBCA stimulated types I and III collagen, fibronectin and α-smooth muscle actin (α-SMA) expression in normal dermal fibroblasts. The results indicate that the monocyte activation induced by GdBCA may be the initial step in the development of GdBCA associated fibrosis in NSF.

Type of MRI contrast, tissue gadolinium, and fibrosis

“…Conditioned media from MRI contrast-treated monocytes stimulated collagen and fibronectin production in addition to ␣-SMA ϩ stress fiber expression regardless of the chelate. Therefore, the transmetallation hypothesis has not been supported by prior in vitro experiments (40). Until our study, there have been no prospective and experimental data to support the contention that one formulation had less propensity to elicit NSF than another.…”

“…Gadodiamide (5 mM) does not differ from any other MRI contrast agent tested with respect to cytokine/chemokine gene expression or the generation of proinflammatory or profibrotic cytokines or chemokines (40). Conditioned media from MRI contrast-treated monocytes stimulated collagen and fibronectin production in addition to ␣-SMA ϩ stress fiber expression regardless of the chelate.…”

Gadolinium toxicity and treatment

“…The acute response component may reflect release of cytokines and chemokines, as has been described in a study by Wermuth et al [47], in which the authors found that all GBCAs induced specific cytokine and chemokine elaboration. This likely explains why apparently a greater range of GBCAs (including macrocyclic agents) cause GDD, unlike both NSF or GSC which are more strongly related to weaker chelates.…”

Gadolinium-based compounds induce NLRP3-dependent IL-1β production and peritoneal inflammation

“…Free Gd that has dissociated from the chelate most likely accounts for the observed effects of the GBCAs, since much higher doses of the chelated forms of Gd were needed to induce IL-1β production. The proinflammatory effects of a GBCA cannot be predicted based upon the chemical structure of the chelate, since the expression of proinflammatory cytokines by monocytes can be induced by GBCAs with either linear or macrocyclic chelates 52. However, a protective effect of chelating agents is supported by the fact that Omniscan, which contains excess chelating agent, was less stimulating than Gd-DTPA, which does not.…”