INTERLEUKIN-6 PLAYS CRITICAL ROLE ON ALDOSTERONE INDUCED MACROPHAGE INFILTRATION IN MYOCARDIUM

Abstract

Objective: An excess of aldosterone results in cardiac remodelling and fibrosis. The key step of aldosterone-induced cardiac fibrosis is macrophage infiltration. In our previous studies, Interleukin-6 (IL-6) is a key mediator in the aldosterone-induced fibrotic process, however the effect of aldosterone on macrophage remains unclear. We investigated whether aldosterone induces the expression of IL-6 and thereby contributes to the macrophage infiltration in myocardium.Design and method: In cell studies, we investigated the possible molecular mechanism how aldosterone induced IL-6 secretion in macrophage and the further effects of macrophage migration and infiltration. Results: Aldosterone significantly induced IL-6 production in THP-1 cells. Intracellular signalling occurred through the mineralocorticoid receptor->PI3K/Akt/p38->NF-kB/NFIL-6 pathway. In macrophage migration and infiltration (RAW 264.7 cells), IL-6 blockage abolished the effect of aldosterone-induced macrophage migration and infiltration. In addition, aldosterone induced macrophage to produce MMP-1 and mmp-9 which through IL-6->JAK/Cox-2->PGE2->EP2/EP4 pathway. To further investigate the role of IL-6 signalling in aldosterone-induced macrophage infiltration, we measured the severity of macrophage infiltration in myocardium in aldosterone infusion mice models including an IL-6 chemical inhibitor and Sgp130 Knockin Transgenic Mice. Mice receiving IL-6 antibody and Sgp130 Knockin Transgenic Mice prevented increased macrophage infiltration in myocardium by aldosterone infusion. Conclusions: IL-6 plays critical role on aldosterone induced macrophage infiltration in myocardium