IL-4-induced transcription factor NFIL3/E4BP4 controls IgE class switching

Abstract

IL-4 signaling promotes IgE class switching through STAT6 activation and the induction of Ig germ-line ε (GLε) transcription. Previously, we and others identified a transcription factor, Nfil3, as a gene induced by IL-4 stimulation in B cells. However, the precise roles of nuclear factor, IL-3-regulated (NFIL3) in IL-4 signaling are unknown. Here, we report that NFIL3 is important for IgE class switching. NFIL3-deficient mice show impaired IgE class switching, and this defect is B-cell intrinsic. The induction of GLε transcripts after LPS and IL-4 stimulation is significantly reduced in NFIL3-deficient B cells. Expression of NFIL3 in NFIL3-deficient B cells restores the impairment of IgE production, and overexpression of NFIL3 in the presence of cycloheximide induces GLε transcripts. Moreover, NFIL3 binds to Iε promoter in vivo. Together, these results identify NFIL3 as a key regulator of IL-4-induced GLε transcription in response to IL-4 and subsequent IgE class switching.IL-4 signal | immunoglobulin | germ-line transcription

Control of the STAT6–BCL6 Antagonism by SWAP-70 Determines IgE Production

“…This is consistent with earlier data demonstrating different binding affinities of STAT6 for the ε (high affinity) and g1 (low affinity) promoter (27). Control PCRs diagnosing promoter regions of IgG2a (Ig2a) and of a proteasome gene, (Pr) (21,22), which lack STAT6 binding sites, did not generate signals (Fig. 4A, 4B).…”

“…Some factors are newly synthesized within about a day after IL-4 signaling and depend on STAT6. De novo protein synthesis is not required for induction of NFIL3 transcription, shown to be important for Iε activation and thus for the switch to IgE (22). NFIL3's activity on Iε also depends on STAT6.…”

“…For full initiation of germline transcript RNA synthesis by RNA Pol II and/or for robust levels of Iε GLT, other factors may have to be assembled over the course of 1-3 days, and thus, the germline transcripts are recognized at about day 3 after induction. One example of such delayed phase factors is NFIL3, whose expression takes ∼24 h (22). The involvement of several transcription factors is known, and we hypothesize that the complete regulation at Iε with STAT6 at its core involves a highly complex platform of factors that act in a delicate balance to fine-tune Iε GLT.…”

p110δ Phosphoinositide 3-Kinase Represses IgE Switch by Potentiating BCL6 Expression

“…Primer sequences for germline transcripts (GLT; g 1 and ε GLT), ε postswitch transcripts, and AID were as described (23). Additional primer sequences were as described: BCL6 (24), Blimp-1 (24), Pax5 (25), Id2 (13), E2A (26), IRF4 (26), NFIL3 (27), Cyclin D2 (28), and CD23 (29). b-actin was used as relative expression control to normalize sample variation.…”

Recruitment of Histone Methyltransferase G9a Mediates Transcriptional Repression of Fgf21 Gene by E4BP4 Protein*

“…In E4bp4 knockout mice, it has been shown that E4BP4 is critical for NK cell development and IgE expression in B cells (12)(13)(14). In addition to its role in the immune system, E4bp4 is also highly expressed in the liver, adipose tissue, and the suprachiasmatic nuclei of the hypothalamus (15).…”