INVOLVEMENT OF STAT3 IN INTERLEUKIN-6-INDUCED IGM PRODUCTION IN A HUMAN B-CELL LINE

Interleukin-6 (IL-6) is an important B-cell growth and differentiation factor. IL-6 treatment of the human lymphoblastoid cell line, SKW6.4, leads to increased IgM production. We have previously shown that IL-6 induces activation of JAK1 and JAK2 in human B cell lines. A chimeric IL-6 receptor, comprised of the intracellular tail of the IL-6 recept or subunit gp130 fused to the extracellular domain of the epidermal gr owth factor (EGF) receptor, was stably transfected into SKW6.4 cells. EGF treatment induced IgM production in cells transfected with an inta ct gp130 cytoplasmic tail, but not in untransfected cells or cells tra nsfected with a cytoplasmic tail lacking all four signal transducers a nd activators of transcription (Stat) binding sites. Moreover, EGF tre atment induced Stat3 phosphorylation in cells transfected with the int act chimeric EGF-gp130 receptor along with induction of DNA-mobility s hift of a classical interferon-gamma-activated site. To define further the relation between Stat3 activation and enhanced IgM production, we determined the effect of chimeric gp130 on the transcriptional activa tion of a genetic element linked to immunoglobulin production, namely the immunoglobulin heavy chain enhancer (IgH-enhancer). Parental as we ll as transfected SKW6.4 cells were transiently transfected with an Ig H-enhancer-luciferase construct. The transcriptional activity of the I gH-luciferase construct was induced upon ligation of the full-length c himeric receptor but not by truncated gp130 receptors. Moreover, the g p130-induced activity of this reporter gene was abrogated by Stat3EE, a mutant Stat3 incapable of binding DNA. These results indicate that I L-6-induced B-cell differentiation, as measured by IgM production, may be controlled by Stat3 proteins.