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 receptor subunit gp130 fused to the extracellular domain of the epidermal growth factor (EGF) receptor, was stably transfected into SKW6.4 cells. EGF treatment induced IgM production in cells transfected with an intact gp130 cytoplasmic tail, but not in untransfected cells or cells transfected with a cytoplasmic tail lacking all four signal transducers and activators of transcription (Stat) binding sites. Moreover, EGF treatment induced Stat3 phosphorylation in cells transfected with the intact chimeric EGF-gp130 receptor along with induction of DNA-mobility shift 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 activation of a genetic element linked to immunoglobulin production, namely the immunoglobulin heavy chain enhancer (IgH-enhancer). Parental as well as transfected SKW6.4 cells were transiently transfected with an IgH-enhancer-luciferase construct. The transcriptional activity of the IgH-luciferase construct was induced upon ligation of the full-length chimeric receptor but not by truncated gp130 receptors. Moreover, the gp130-induced activity of this reporter gene was abrogated by Stat3EE, a mutant Stat3 incapable of binding DNA. These results indicate that IL-6-induced B-cell differentiation, as measured by IgM production, may be controlled by Stat3 proteins.
Faris
M
M
Department of Medicine, UCLA School of Medicine 90024, USA.
Kokot
N
N
Stahl
N
N
Nel
A E
AE
D000209:Acute-Phase Proteins / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000276:immunology*; D004815:Epidermal Growth Factor / Q000276:immunology; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007075:Immunoglobulin M / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology; D010766:Phosphorylation; D018123:Receptors, Interleukin / Q000276:immunology; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins / Q000276:immunology; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000276:immunology*; D014162:Transfection; D014407:Tumor Cells, Cultured
D000209:Acute-Phase Proteins; D015703:Antigens, CD; D004268:DNA-Binding Proteins; C494199:IL6ST protein, human; D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D018123:Receptors, Interleukin; D019947:Receptors, Interleukin-6; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D050822:Cytokine Receptor gp130; D004815:Epidermal Growth Factor