Effects of mercuric chloride on the regulation of expression of the acute phase response components alpha(1)-acid glycoprotein and C/EBP transcription factors.

We have previously shown that in response to treatment with HgCl(2), the adult mouse liver exhibits both transcriptional and translational regulation of the acute phase response genes. In this study we asked whether the heavy metal treatment affects the regulation of the C/EBP transcription factors which play a key role in regulation of the acute phase response gene. Our studies have shown that the AGP gene is transcriptionally activated while transcription of the CCAAT/enhancer-binding trans-activating protein (C/EBP)alpha gene is slightly down-regulated and that of the C/EBPbeta gene does not respond. Both the C/EBPalpha and C/EBPbeta mRNAs produce multiple isoforms possibly by alternative translation initiation (ATI) of multiple internal AUG initiation sites. The C/EBPbeta mRNA appears to be stabilized. Although similar regulatory processes occur in response HgCl(2) vs. LPS, our data suggest that the translational processes (ATI) are differentially affected. In addition, a major difference lies in the fact that the C/EBPbeta gene is not transcriptionally activated by HgCl(2). Our data show decreased binding activity and pool levels of the C/EBPalpha isoform (p42(C/EBPalpha)) and increased binding activity and pool levels of C/EBPbeta isoform (p35(C/EBPbeta)) in response to HgCl(2). We propose that this isoform may be involved in the regulation of AGP gene expression in response to heavy metals and that there is a significant difference between the HgCl(2)-mediated and LPS-mediated inflammatory response.