Lineage-Specific Modulation of Interleukin 4 Signaling by Interferon Regulatory Factor 4

Abstract

Interleukin (IL)-4 is an immunoregulatory cytokine that exerts distinct biological activities on different cell types. Our studies indicate that interferon regulatory factor (IRF)-4 is both a target and a modulator of the IL-4 signaling cascade. IRF-4 expression is strongly upregulated upon costimulation of B cells with CD40 and IL-4. Furthermore, we find that IRF-4 can interact with signal transducer and activator of transcription (Stat)6 and drive the expression of IL-4–inducible genes. The transactivating ability of IRF-4 is blocked by the repressor factor BCL-6. Since expression of IRF-4 is mostly confined to lymphoid cells, these data provide a potential mechanism by which IL-4–inducible genes can be regulated in a lineage-specific manner.

p38 Mitogen-activated Protein Kinase Regulates Interleukin-4-induced Gene Expression by Stimulating STAT6-mediated Transcription

“…STAT6 has been shown to cooperate with several transcription factors, but the mechanisms of cooperation between various transcription factors differ significantly. For example, C/EBP␤ stabilizes the DNA binding of STAT6, whereas the effects of interferon regulatory factor-4 and NF-B are directed to transcriptional activation and involve physical interaction with STAT6 (7,10,11).…”

“…For example, the promoters of human CD23 and Ig⑀ genes contain in addition to STAT6-binding sites, also response elements for CCAAT/enhancer-binding protein ␤ (C/EBP␤) NF-B, interferon regulatory factor-4, and B cell-specific activator protein (Pax5) (6,7). STAT6 appears to be the only transcription factor that is functionally regulated by IL-4, whereas the other factors are either regulated by costimulatory signals as exemplified by CD40-mediated regulation of NF-B or through transcriptional regulation (8,9).…”

T Cell Receptor Engagement Leads to the Recruitment of IBP, a Novel Guanine Nucleotide Exchange Factor, to the Immunological Synapse

“…Protein Purification, Antibodies, Cell Extracts, and Protein Assays-GST-IBP fusion proteins were expressed in E. coli DH5␣ and affinitypurified on glutathione-agarose beads (Sigma), as described previously (25). HA epitope-tagged IBP (full-length wild-type) was expressed in 293T cells and affinity-purified on immobilized anti-HA monoclonal antibody (clone 3F10; anti-HA affinity matrix; Roche Applied Science) according to the procedures recommended by the manufacturer.…”

Repression of IRF-4 target genes in human T cell leukemia virus-1 infection

“…IRF-4 is involved with PU.1 in the transcriptional regulation of B cell specific genes such as immunoglobulin k and g light chains, CD20 and CD23 (Brass et al, 1996;Eisenbeis et al, 1995;Gupta et al, 1999Gupta et al, , 2001Himmelmann et al, 1997;Meraro et al, 1999;Nagulapalli and Atchison, 1998). IRF-4 transactivating complexes are also involved in the regulation of IL-1b and ISG15 in macrophages (Marecki et al, 2001;Rosenbauer et al, 1999).…”