C/EBPzeta (CHOP/Gadd153) is a negative regulator of LPS-induced IL-6 expression in B cells.

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.