Department of Oral Microbiology and Immunology, DRI, and BK21 Plus Program, School of Dentistry, Seoul National University, Seoul, South Korea.
Department of Agricultural Biotechnology and Research Institute for Agriculture and Life Sciences, Seoul National University, Seoul, South Korea.
Front Immunol. 2020 Oct 2;11:564699. doi: 10.3389/fimmu.2020.564699. eCollection 2020.
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 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 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.
B 细胞激活因子 (BAFF) 在 B 细胞的存活、分化和抗体分泌中发挥着关键作用。具有 B 细胞有丝分裂原特性的微生物产物可以通过刺激辅助细胞（如树突状细胞 (DC)）间接促进 B 细胞的扩增和激活，从而诱导 BAFF。尽管细菌脂蛋白与脂多糖 (LPS) 一样是有效的 B 细胞有丝分裂原，但尚不确定它们是否可以刺激 DC 诱导 BAFF 表达。在这里，我们评估了细菌脂蛋白对小鼠骨髓来源的 DC 中 BAFF 表达的影响。与野生型菌株相比，脂蛋白缺陷型 突变体诱导的膜结合 BAFF (mBAFF) 和 mRNA 的表达水平相对较低，这表明细菌脂蛋白可以正向调节 BAFF 的诱导。模拟细菌脂蛋白的合成脂肽 Pam2CSK4 和 Pam3CSK4 剂量依赖性地诱导 BAFF 表达，其 BAFF 诱导能力与 LPS 在 DC 中的诱导能力相当。脂肽诱导的 BAFF 诱导高于其他微生物相关分子模式（包括肽聚糖、鞭毛蛋白、酵母聚糖、脂磷壁酸和聚 I:C）的诱导。Pam3CSK4 以剂量和时间依赖的方式诱导 mBAFF 和可溶性 BAFF 的表达。TLR2 或 MyD88 缺陷型小鼠来源的 DC 中完全不存在 Pam3CSK4 诱导的 BAFF 表达。在各种 MAP 激酶抑制剂中，只有 JNK 抑制剂阻断了 Pam3CSK4 诱导的 BAFF mRNA 表达，而阻断 ERK 或 p38 激酶的抑制剂则没有这种作用。此外，Pam3CSK4 增加了 NF-κB 和 Sp1 的 DNA 结合活性，但 C/EBP 的则没有。Pam3CSK4 诱导的 BAFF 启动子活性 TLR2/1 被 NF-κB 或 Sp1 抑制剂阻断。总之，这些结果表明，细菌脂蛋白通过 TLR2/MyD88/JNK 信号通路诱导 BAFF 的表达，导致 DC 中 NF-κB 和 Sp1 的激活，而由细菌脂蛋白刺激的 DC 衍生的 BAFF 诱导 B 细胞增殖。
