LEUKEMIA INHIBITORY FACTOR, A POTENT CARDIAC HYPERTROPHIC CYTOKINE, ACTIVATES THE JAK STAT PATHWAY IN RAT CARDIOMYOCYTES/

Leukemia inhibitory factor (LIF) is a member of the interleukin-6 fami ly of cytokines, which induces a wide range of responses in a variety of cells. The aim of this study was to investigate whether LIF induces cardiomyocyte hypertrophy and transmits signals through the JAK/STAT (indicating just another kinase/signal transducer and activator of tra nscription) pathway in primary cultured neonatal rat cardiomyocytes. L IF increased protein content and [H-3]phenylalanine uptake in cardiomy ocytes in a dose-dependent manner. LIF (10(3) U/mL) induced rapid tyro sine phosphorylation of gp130, JAK1, JAK2, STAT1, and STAT3 but not Ty k2 or STAT2. LIF also induced autokinase activity of JAK1 in a time-de pendent manner. Gel shift assays for interferon gamma activation site/ interferon-stimulated responsive element and sis-inducible element (SI E) revealed that LIF induced dimerization of STAT1 and STAT3 and forma tion of sis-inducing factor complexes, which subsequently interacted w ith SIE in the promoter. Preincubation with anti-STAT1 and anti-STAT3 antibodies inhibited the binding of SIF complexes. In conclusion, LIF induces cardiac hypertrophy and directly stimulates the JAK/STAT pathw ay in cardiomyocytes.