Abstract
B-cell activating factor (BAFF) plays a crucial role in survival, differentiation, and antibody secretion of B cells. Microbial products with B-cell mitogenic properties can indirectly promote expansion and activation of B cells by stimulating accessory cells, such as dendritic cells (DCs), to induce BAFF. Although bacterial lipoproteins are potent B-cell mitogen like lipopolysaccharides (LPSs), it is uncertain whether they can stimulate DCs to induce BAFF expression. Here, we evaluated the effect of bacterial lipoproteins on BAFF expression in mouse bone marrow–derived DCs. Lipoprotein-deficient Staphylococcus aureus mutant induced relatively low expression level of membrane-bound BAFF (mBAFF) and the mRNA compared with its wild-type strain, implying that bacterial lipoproteins can positively regulate BAFF induction. The synthetic lipopeptides Pam2CSK4 and Pam3CSK4, which mimic bacterial lipoproteins, dose-dependently induced BAFF expression, and their BAFF-inducing capacities were comparable to those of LPS in DCs. Induction of BAFF by the lipopeptide was higher than the induction by other microbe-associated molecular patterns, including peptidoglycan, flagellin, zymosan, lipoteichoic acid, and poly(I:C). Pam3CSK4 induced both mBAFF and soluble BAFF expression in a dose- and time-dependent manner. BAFF expression by Pam3CSK4 was completely absent in DCs from TLR2- or MyD88-deficient mice. Among various MAP kinase inhibitors, only JNK inhibitors blocked Pam3CSK4-induced BAFF mRNA expression, while inhibitors blocking ERK or p38 kinase had no such effect. Furthermore, Pam3CSK4 increased the DNA-binding activities of NF-κB and Sp1, but not that of C/EBP. Pam3CSK4-induced BAFF promoter activity via TLR2/1 was blocked by NF-κB or Sp1 inhibitor. Collectively, these results suggest that bacterial lipoproteins induce expression of BAFF through TLR2/MyD88/JNK signaling pathways leading to NF-κB and Sp1 activation in DCs, and BAFF derived from bacterial lipoprotein-stimulated DCs induces B-cell proliferation.
Highlights
B cells are essential components for immune responses, including antibody production, antigen presentation, lymphoid organogenesis, cytokine expression, and T-cell differentiation [1]
We initially examined whether bacterial lipoproteins are involved in BAFF production of dendritic cells (DCs) using a mutant strain of lipoproteindeficient S. aureus (Dlgt)
Because prolipoprotein diacylglycerol transferase (Lgt) is known to mediate the transfer of diacylglycerol to the sulfhydryl moiety of a cysteine residue in the lipobox of preprolipoproteins, which leads to maturation of bacterial lipoprotein, the Dlgt strain exhibited no evidence of lipoprotein synthesis [24]
Summary
B cells are essential components for immune responses, including antibody production, antigen presentation, lymphoid organogenesis, cytokine expression, and T-cell differentiation [1]. LPS can indirectly promote proliferation and activation of B cells by inducing B-cell activating factor (BAFF) production from antigen-presenting cells, including dendritic cells (DCs) and macrophages [5,6,7]. Soluble BAFF (sBAFF) binds to three distinct receptors on B cells: BAFF-receptor (BAFF-R), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), and B-cell maturation antigen (BCMA) [14]. As these BAFF receptors have different biological functions in B cells, their distinct expression patterns during B-cell development determine the roles of BAFF at each developmental stage [11]. Because TACI is predominantly expressed on mature B cells, such as plasma cells, but not on immature B cells, BAFF binding to TACI promotes class-switch recombination and survival of plasma cells [13, 15]
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