Interleukin 6 induces secretion of IgG1 by coordinated transcriptional activation and differential mRNA accumulation.
The molecular mechanism by which interleukin 6 (IL-6) induces terminal differentiation of B cells was investigated in a subpopulation of the clonal human B-lymphoblastoid cell line CESS selected for high density of cell surface IgG1. Induction of CESS cells with IL-6 resulted in a 15-fold preferential accumulation of secreted-specific gamma 1 (gamma 1s) mRNA but not of the alternatively processed membrane-specific gamma 1 (gamma 1m) mRNA. Similarly, microseconds mRNA but not the microns mRNA of the nonproductively rearranged mu heavy-chain allele was also increased. Accompanying the differential accumulation of gamma 1s mRNA was a 4.5-fold increase in lambda light-chain mRNA, leading to secretion of IgG1. Analyses of transcription in isolated nuclei demonstrated that transcriptional activation was the primary mechanism for quantitative increase of immunoglobulin mRNAs (5.5-fold for gamma 1 and mu and at least 2-fold for lambda). Since polymerase loading is diminished by 75% before reaching the downstream gamma 1m polyadenylylation site in CESS cells, irrespective of IL-6 induction, transcriptional pausing/termination appears intrinsic and contributes to the selection of gamma 1s and gamma 1m polyadenylylation sites in activated B cells. Furthermore, differential mRNA stabilization is likely to contribute to the alteration of the gamma 1s/gamma 1m mRNA ratio at IL-6 induction.
Raynal
M C
MC
Brookdale Center for Molecular Biology, New York, NY 10029.
Liu
Z Y
ZY
Hirano
T
T
Mayer
L
L
Kishimoto
T
T
Chen-Kiang
S
S
D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D001483:Base Sequence; D015152:Blotting, Northern; D002460:Cell Line; D005786:Gene Expression Regulation; D005803:Genes, Immunoglobulin / Q000187:drug effects*; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis* / Q000235:genetics; D015850:Interleukin-6 / Q000494:pharmacology*; D008969:Molecular Sequence Data; D015345:Oligonucleotide Probes / Q000138:chemical synthesis; D010957:Plasmids; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*
D007074:Immunoglobulin G; D015850:Interleukin-6; D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D011994:Recombinant Proteins