Pro-inflammatory cytokine secretion induced by amyloid transthyretin in human cardiac fibroblasts.

ABSTRACT

Extracellular aggregates of wild-type human transthyretin are associated with heart diseases such as wild-type transthyretin (TTR)-derived amyloidosis (ATTR-wt). Due to their strategic location, cardiac fibroblasts act as sentinel cells that sense injury and activate the inflammasome. No studies of the effects of TTR amyloid aggregation on the secretion of inflammatory factors by primary human cardiac fibroblasts (hCFs) have been reported yet. The intracellular internalization of TTR aggregates, which correspond to the early stage of ATTR-wt, were determined using immunofluorescence and Western blotting of cell lysates. A further objective of this study was to analyze the secretion of inflammatory factors by hCFs after analysis of TTR amyloid aggregation using X-MAP® Luminex Assay techniques. We show that TTR aggregates are internalized in hCFs and induce the secretion of both Brain Natriuretic Peptide (BNP) and N-terminal pro B-type Natriuretic Peptide(NT-proBNP). Also, pro-inflammatory mediators such as interleukin-6 (IL-6) and IL-8 are secreted without significant changes in the levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). In conclusion, these findings suggest that IL-6 and IL-8 play important roles in the development of ATTR-wt, and indicate that IL-6 in particular could be a potentially important therapeutic target in patients with ATTR-wt.