The different effect of pharmacological or low-doses of IFN-γ in endothelial cells are mediated by different intracellular signaling pathways

Abstract

Interferon (IFN)-{gamma} is a proinflammatory cytokine with a crucial role in intercellular communication during innate and acquired immune responses. IFN-{gamma} interacts with many cell types, among which endothelial cells. Here, we show that pharmacological and low-dose kinetically activated (SKA) IFN-{gamma} exert different effects on endothelial cells by activating different signal transduction pathways. Pharmacological concentrations of IFN-{gamma} activate JAK/STAT pathway, inducing the overexpression of the CDKN1A p21, which in turn inhibits cell growth. Conversely, low-dose SKA IFN-{gamma} does not activate the canonical JAK/STAT pathway but induces the phosphorylation of ERK. ERK activation is responsible for the induction of endothelial cell migration. Interestingly, ERK activation occurs only in the presence of kinetically activate low-dose IFN-{gamma}, underlying the importance of mechanical forces to potentiate IFN-{gamma} activity.