ACTIVATION OF JAK-STAT AND MAP KINASES BY LEUKEMIA INHIBITORY FACTOR THROUGH GP130 IN CARDIAC MYOCYTES

Background Interleukin (IL)-6-related cytokines share gp130 as the sig nal-transducing protein. Downstream of gp130, two signal-transducing p athways have been recognized, the Janus kinase-signal transducer and a ctivator of transcription (JAK-STAT) pathway and the Ras-mitogen-activ ated protein kinase (MAPK) pathway. To determine whether these two sig naling pathways through gp130 are present in cardiac myocytes, we exam ined 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-g p130, anti-JAK1, or anti-STAT3 antibody and blotted with anti-phosphot yrosine antibody. Tyrosine phosphorylation of gp130, JAK1, and STAT3 w as observed after LIF stimulation in cardiac myocytes. MAPKs were maxi mally activated 5 minutes after LIF stimulation. Furthermore, anti-gp1 30 antibody significantly inhibited the LIF-induced activation of JAK1 , STAT3, and MAPKs. To examine whether these signaling pathways were a lso activated in the adult heart in vivo, LIF was injected intravenous ly into a 6-week-old mouse, and the heart was examined subsequently. g p130, 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 downstream of gp130 in car diac myocytes and are rapidly activated by LIF both in vitro and in vi vo. Activation of gp130 constitutes a novel signaling pathway in cardi ac myocytes.