Analysis of transforming growth factor-beta1-induced Ig germ-line gamma2b transcription and its implication for IgA isotype switching
Department of Molecular Genetics and Microbiology
Animals; Base Sequence; Core Binding Factor Alpha 3 Subunit; DNA-Binding Proteins; E1A-Associated p300 Protein; Electrophoretic Mobility Shift Assay; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin G; Mice; Mice, Inbred BALB C; Molecular Sequence Data; Nuclear Proteins; Promoter Regions (Genetics); Reverse Transcriptase Polymerase Chain Reaction; Smad3 Protein; Smad4 Protein; Trans-Activators; Transcription Factors; *Transcription, Genetic; Transfection; Transforming Growth Factor beta
Life Sciences | Medicine and Health Sciences | Women's Studies
Transforming growth factor (TGF)-beta1 directs class switch recombination (CSR) to IgG2b as well as to IgA. Smad3/4, Runx3 and p300 mediate TGF-beta1-induced germ-line (GL) alpha transcription leading to IgA expression. However, the molecular mechanisms by which TGF-beta1 induces IgG2b CSR are unknown. We used luciferase reporter plasmids to investigate how TGF-beta1 regulates the activity of the promoter for GL transcripts of IgG2b constant gene (GLgamma2b promoter). Similarly to the GLalpha promoter, overexpression of Smad3/4 and Runx3 enhances TGF-beta1-induced GLgamma2b promoter activity. Mutation analysis of the promoter identified likely Smad- and Runx3-binding sites. Also similar to the GLalpha promoter, overexpression of p300 enhances Smad3/4-mediated promoter activity, whereas E1A represses promoter activity. Since these regulation mechanisms underlying both GLalpha and GLgamma2b transcription are similar, we explored the possibility that TGF-beta1 induces IgA CSR via transitional IgG2b CSR. TGF-beta1 enhances the expression of both Ialpha-Cmu and Ialpha-Cgamma2b circle transcripts, indicative of direct (Smu-->Salpha) and sequential CSR (Smu-->Sgamma2b-->Salpha).
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Citation: Eur J Immunol. 2005 Mar;35(3):946-56. Link to article on publisher's site