Gao Hongwei, Schwartz Richard C
Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI 48824, United States.
Mol Immunol. 2009 Dec;47(2-3):390-7. doi: 10.1016/j.molimm.2009.09.002. Epub 2009 Sep 25.
C/EBPzeta was originally identified as a gene induced upon DNA damage and growth arrest. It has been shown to be involved in the cellular response to endoplasmic reticulum stress. Because of sequence divergence from other C/EBP family members in its DNA-binding domain and its consequent inability to bind the C/EBP consensus-binding motif, C/EBPzeta can act as a dominant negative inhibitor of other C/EBPs. C/EBP transactivators are essential to the expression of many proinflammatory cytokines and acute phase proteins, but a role for C/EBPzeta in regulating their expression has not been described. We found that expression of C/EBPzeta is induced in response to LPS treatment of B cells at both the mRNA and protein levels. Correlating with the highest levels of C/EBPzeta expression at 48 h after LPS treatment, there is an increased association of C/EBPzeta with C/EBPbeta, and both the abundance of C/EBP DNA-binding species and IL-6 expression are downregulated. Furthermore, ectopic expression of C/EBPzeta inhibited C/EBPbeta-dependent IL-6 expression from both the endogenous IL-6 gene and an IL-6 promoter-reporter. These results suggest that C/EBPzeta functions as negative regulator of IL-6 expression in B cells and that it contributes to the transitory expression of IL-6 that is observed after LPS treatment.
C/EBPζ最初被鉴定为一种在DNA损伤和生长停滞时被诱导的基因。已证明它参与细胞对内质网应激的反应。由于其DNA结合结构域与其他C/EBP家族成员存在序列差异，因而无法结合C/EBP共有结合基序，C/EBPζ可作为其他C/EBP的显性负性抑制剂。C/EBP反式激活因子对许多促炎细胞因子和急性期蛋白的表达至关重要，但C/EBPζ在调节它们表达中的作用尚未见报道。我们发现，用脂多糖（LPS）处理B细胞后，C/EBPζ的表达在mRNA和蛋白质水平均被诱导。与LPS处理后48小时C/EBPζ表达的最高水平相关，C/EBPζ与C/EBPβ的结合增加，且C/EBP DNA结合物种的丰度和白细胞介素-6（IL-6）的表达均下调。此外，C/EBPζ的异位表达抑制了内源性IL-6基因和IL-6启动子报告基因中依赖C/EBPβ的IL-6表达。这些结果表明，C/EBPζ在B细胞中作为IL-6表达的负调节因子发挥作用，并且它有助于LPS处理后观察到的IL-6的短暂表达。
