Human IgGs induce synthesis and secretion of IgGs and neonatal Fc receptor in human umbilical vein endothelial cells

Abstract

Human IgGs are increasingly used in the therapy of many different immune and inflammatory diseases, however their mechanism of action still remains unclear in most diseases. To gain insight into the mechanism by which IgGs might also exert their effects on endothelial cells, we tested human IgGs on human umbilical vein endothelial cells (HUVECs). IgGs induced a time-dependent increase in the synthesis and secretion of IgGs, together with a marked angiogenic-like transformation of HUVECs that was maximal after a 20-h incubation. IgGs stimulated IG gene transcription without affecting the process of gene rearrangement, already present in control HUVECs. The mechanism involved the activation of transcription factors with the increased expression of HSP90, HSP70 and inactive MMP-9 responsible for the phenotypic differentiation associated with the most intense IgG synthesis and secretion. However, even a short incubation with IgGs followed by recovery of cells was sufficient to trigger and sustain in time the synthesis and secretion of new IgGs, independently of the angiogenic-like transformation visible only when cells were continuously exposed to IgGs. Under the stimulus of IgGs, specific secretory pathways were also activated in HUVECs together with the expression of FcRn, which was always associated with IgGs of new synthesis, forming complexes that were also secreted. Our results disclose a so far unknown and unexpected mechanism of IgGs on HUVECs that behave as Ig-producing immune cells. Results might have relevance for the effects that IgGs also exert in vivo in physiological conditions.

Keywords: Cell differentiation; Heat shock proteins; Immunoglobulin gene; MEK-ERK pathway; Proto-oncogene proteins c-akt; Secretory pathway; Vascular endothelium.