C/EBPγ has a stimulatory role on the IL-6 and IL-8 promoters

CCAAT/enhancer-binding protein gamma (C/EBPgamma) is an ubiquitously expressed member of the C/EBP family of transcription factors that has been shown to be an inhibitor of C/EBP transcriptional activators and has been proposed to act as a buffer against C/EBP-mediated activation. We have now unexpectedly found that C/EBPgamma dramatically augments the activity of C/EBPbeta in lipopolysaccharide induction of the interleukin-6 and interleukin-8 promoters in a B lymphoblast cell line. This activating role for C/EBPgamma is promoter-specific, neither being observed in the regulation of a simple C/EBP-dependent promoter nor the TNFalpha promoter. C/EBPgamma activity also shows cell-type specificity with no activity observed in a macrophage cell line. Studies with chimeric C/EBP proteins implicate the formation of a heterodimeric leucine zipper between C/EBPbeta and C/EBPgamma as the critical structural feature required for C/EBPgamma stimulatory activity. These findings suggest a unique role for C/EBPgamma in B cell gene regulation and, along with our previous observation of the ability of C/EBP basic region-leucine zipper domains to confer lipopolysaccharide inducibility of interleukin-6, suggest that the C/EBP leucine zipper domain has a role in C/EBP function beyond allowing dimerization between C/EBP family members.