Activation of JAK-STAT and MAP Kinases by Leukemia Inhibitory Factor Through gp130 in Cardiac Myocytes

Abstract

BACKGROUND: Interleukin (IL)-6-related cytokines share gp130 as the signal-transducing protein. Downstream of gp130, two signal-transducing pathways have been recognized, the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway and the Ras-mitogen-activated protein kinase (MAPK) pathway. To determine whether these two signaling pathways through gp130 are present in cardiac myocytes, we examined their activation by using leukemia inhibitory factor (LIF), which is a member of the IL-6 cytokine family. METHODS AND RESULTS: Lysates from neonatal rat cardiac myocytes were immunoprecipitated with anti-gp130, anti-JAK1, or anti-STAT3 antibody and blotted with anti-phosphotyrosine antibody. Tyrosine phosphorylation of gp130, JAK1, and STAT3 was observed after LIF stimulation in cardiac myocytes. MAPKs were maximally activated 5 minutes after LIF stimulation. Furthermore, anti-gp130 antibody significantly inhibited the LIF-induced activation of JAK1, STAT3, and MAPKs. To examine whether these signaling pathways were also activated in the adult heart in vivo, LIF was injected intravenously into a 6-week-old mouse, and the heart was examined subsequently. gp130, STAT3, and MAPKs were activated in the heart after LIF treatment. CONCLUSIONS: These results demonstrate for the first time that a JAK-STAT pathway and a MAPK pathway are present down-stream of gp130 in cardiac myocytes and are rapidly activated by LIF both in vitro and in vivo. Activation of gp130 constitutes a novel signaling pathway in cardiac myocytes.