Interleukin-6 family of cytokines mediate angiotensin II-induced cardiac hypertrophy in rodent cardiomyocytes

This study was designed to investigate whether angiotensin II induces the i nterleukin (IL)-6 family of cytokines in cardiac fibroblasts and, if so, wh ether these cytokines can augment cardiac hypertrophy. Angiotensin II incre ased IL-6, leukemia inhibitory factor (LIF) and cardiotrophin-1 mRNA by 6.5 -, 10.2-, and 2.0-fold, respectively, but did not affect IL-11, ciliary neu rotrophic factor, or oncostatin M in cardiac fibroblasts, Enzyme-linked imm unosorbent assay revealed that angiotensin II-stimulated conditioned medium from cardiac fibroblasts contained 9.3 ng/ml IL-6 at 24 h, which was 24-fo ld higher than the control. It phosphorylated gp130 and STAT3 in cardiomyoc ytes, which was reduced with RX435 (anti-gp130 blocking antibody). It incre ased [H-3]phenylalanine uptake and cell area by 44% and 86% in cardiomyocyt es compared with mock medium. RX435 suppressed these increases by 26% and 3 8%, while TAK044 (endothelin-A/B-R blocker) suppressed them by 52% and 52%, respectively. Antisense oligonucleotides against LIF and cardiotrophin-1 b locked their up-regulation, and attenuated the conditioned medium-induced i ncrease in [H-3]phenylalanine uptake by 21% and 13%, respectively. The comb ination of antisense oligonucleotides to LIF and cardiotrophin-1 decreased their uptake by 33%, These results indicated that angiotensin II induced IL -6, LIF, and cardiotrophin-1 in cardiac fibroblasts, and that these cytokin es, particularly LIF and cardiotrophin-1, activated gp130-linked signaling and contributed to angiotensin II-induced cardiomyocyte hypertrophy.