Consequently, some DLBCLs accumulate somatic mutations in the IRF4 binding region of BCL6, thereby causing high expression of BCL6 to be maintained in the face of IRF4 expression. Some IRFs also participate in signal transduction through pattern recognition receptors, such as the Toll-like receptors (TLRs). IRF4 (also known as pip, MUM1, LSIRF, NFEM5, and ICSAT) is an IRF family member that is restricted in expression to the immune system, MHP 133 a property it shares with the closely related family member IRF8. IRF4 and IRF8 have evolved as critical mediators of lymphoid, myeloid, and dendritic cell development (1C5). Unlike other IRF family members, IRF4 is not induced by interferon but rather by diverse mitogenic stimuli, including antigen receptor engagement, lipopolysaccharide, and CD40 signaling (6C8). These stimuli all activate the NF-kB pathway, which leads to promoter activation by NF-kB heterodimers (7C10). In addition, transcription can be activated by the cytokine IL-4, implicating the transcription factor STAT6 in its activation (7, 8). The abundance of IRF4 varies within the hematopoietic system in a lineage and stage-specific manner (Figure 1). In mature B cells, expression is repressed by the Mitf transcription factor (11). Consequently, and (24, 25). Additional protein-protein interactions between IRF4 and other regulatory factors modulate its DNA binding properties and/or transactivation potential. The EICE site in the Ig 3 kappa light chain enhancer is adjacent to a binding site MHP 133 for the E-box protein E47, encoded by the gene (26). Protein-protein interactions between IRF4 and E47 increase the ability of these factors to activate transcription through this element by 50C100-fold (26). Similar transcriptional synergy between IRF4 and E47 operates at the and loci (25, 27). In transient transfection studies, IRF4 can also interact and cooperate with STAT6 to induce the Bmpr1b STAT6-responsive gene promoter in T cells (29). Finally, the ability of IRF4 to bind to the promoters of the pro-inflammatory cytokines IL-17 and IL-21 can be blocked by binding of IRF4 to a small GTPase termed IBP (30, 31). Interestingly, mice deficient in IBP develop a virulent autoimmune disease involving excessive IL-17 and IL-21 production, but breeding these mice to an IRF4 knockout strain MHP 133 ameliorates this disease (30). IRF4 is an essential regulator at multiple steps in B cell differentiation. Both IRF4 and IRF8 are required in a redundant fashion to regulate the pre-B cell transition (32). B cells deficient in both IRF4 and IRF8 are arrested at the large pre-B cell stage in which cells have undergone VDJ recombination at the immunoglobulin heavy chain locus, express cytoplasmic immunoglobulin heavy chain, have elevated expression of the pre-B cell receptor (preBCR) on the cell surface, and are rapidly proliferating. Mechanistically, IRF4 or IRF8 downregulate expression of preBCR components by inducing the Ikaros and Aiolos transcription factors, thereby terminating preBCR-driven proliferation (33). In small pre-B cells, IRF4 activates immunoglobulin light chain gene rearrangement by directly binding to the 3 kappa and lambda immunoglobulin enhancers (34). Additionally, IRF4 upregulates CXCR4, the receptor for the chemokine SDF-1. The potential consequence is the migration of small pre-B cells towards bone marrow stromal cells that express SDF-1 and away from IL-7-expressing stroma cells that lack SDF-1 (35). Such migration could further augment immunoglobulin light chain gene rearrangement since IL-7 inhibits this process (34). The ability of IRF4 to promote immunoglobulin light chain rearrangement serves an additional important function in central B cell tolerance by editing self-reactive B cell receptors (36). Exposure of a self-reactive B cell to its cognate self antigen upregulates IRF4, promoting immunoglobulin light chain rearrangement and replacement, which enables some B cell progeny to escape deletion and populate the peripheral lymphoid organs. IRF4 plays a critical and nonredundant role in the adaptive immune responses of mature B cells (Figure 1) (6). Without.