ABSTRACT
Background and purpose: To investigate the role of
bromodomain-containing protein 4 (Brd4) in regulating B cell
differentiation and its therapeutic potential for B cell-mediated
autoimmune diseases such as systemic lupus erythematosus (SLE).
Experimental Approach: Human and murine B cells were purified
and cultured with different stimuli. B cell surface markers,
proliferation and apoptosis were estimated by flow cytometry. Gene
expression was measured by quantitative real-time PCR. Brd4 binding
sites were analysed by the luciferase reporter assay and the chromatin
immunoprecipitation (ChIP) assay. PFI-1 or JQ1 was used to inhibit Brd4.
Mice with B cell-specific deletion of the Brd4 gene
(Brd4flox/floxCD19-Cre+/-) and
MRL/lpr mice were used to perform the in vivo experiments.
Key Results: Brd4 inhibition suppressed plasmablast-mediated
plasma cell differentiation but did not influence proliferation or
apoptosis in healthy human and murine CD19+ B cells. PFI-1 treatment
reduced the secretion of IgG and IgM in the supernatants of
costimulation-induced B cells. Mechanistically, Brd4 regulates the
terminal differentiation of B cells into plasma cells by targeting
BLIMP1 by directly binding and activating the endogenous BLIMP1
promoter. Interestingly, PFI-1 treatment decreased the percentages of
plasmablasts and plasma cells from patients with SLE. PFI-1
administration reduced the percentages of plasma cells,
hypergammaglobulinemia and attenuated nephritis in MRL/lpr mice.
Pristane-injected
Brd4flox/floxCD19-Cre+/- mice
exhibited improved nephritis and reduced percentages of plasma cells.
Conclusions and Implications: Brd4 is an essential factor in
regulating plasma cell differentiation. Brd4 inhibition may be a
potential new strategy for the treatment of B cell-associated autoimmune
disorders, including SLE.
Abbreviations: Brd4, bromodomain-containing protein 4; SLE,
systemic lupus erythematosus; BLIMP1, B lymphocyte-induced maturation
protein 1; XBP1, X-box-binding protein 1; IRF4, interferon regulatory
factor 4