Hepatic expression of CMP-NeuAc:Gal beta 1,4GlcNAc alpha 2,6-sialyltransferase (ST6Gal I) is induced as part of the acute phase response in mammals by mechanisms that remain poorly understood. Previous work suggests that murine liver ST6Gal I mRNA contains an additional and novel region that is not found on ST6Gal I mRNA from human HepG2 hepatoma cells and from rat liver. This novel region, residing 5' of the common Exon I sequence, is encoded by a discrete upstream exon, Exon H. Here we provide evidence that the Exon H-containing transcript is the murine counterpart of the human and rat ST6Gal I mRNAs transcribed from the hepatic-specific promoter, P1. Exon H-containing ST6Gal I mRNA is expressed in all three mice strains examined: balb/c, C57B46, and 129Sv. Furthermore, murine RNA tissue survey indicates that presence of Exon H-containing transcripts is restricted to the liver. When mice are subjected to subcutaneous injection of turpentine to elicit the hepatic acute phase response, greater than 4-fold elevation in liver ST6Gal I mRNA was observed. Consistent with the view that Exon H-containing transcripts is regulated by the murine P1 promoter, 5'-RACE analysis indicates that the majority of these transcripts contains the Exon H sequence. This is consistent with the view that Exon H-containing transcripts are regulated by the murine P1 region. To assess the mechanism of ST6Gal I response in the hepatic acute phase reaction, mice harboring lesions in both alleles of the IL-6 gene were examined. IL-6(-/-) animals expressed normal levels of ST6Gal I mRNA in liver, with Exon H-containing transcripts remaining the predominant mRNA isoform. However, hepatic ST6Gal I is not elevated upon turpentine injection in the IL-6(-/-) animals. These results indicate that ST6Gal I induction in mouse liver during the acute phase reaction is mediated predominantly by the IL-6 pathway, and results in the induction of the Exon H-containing class of ST6Gal I mRNA that is specific to the liver.

ST6Gal I (β-galactoside α2,6-sialyltransferase, ST6N) elaborates the ubiquitously expressed α2,6-sialyl linkage. A number of ST6Gal I mRNA isoforms, differing only in their 5′-UT regions, is transcribed from a single mouse gene, Siat1. In B-lineage cells, α2,6-sialic acid serves as extracellular ligand for CD22, a participant in cell activation via an intracellular signaling network of tyrosine kinases and SHP phosphastase. Activation and terminal differentiation of mature B cells into plasma cells is accompanied by the appearance of at least four distinct ST6Gal I mRNA isoforms. Resting splenic B-lymphocytes isolated from 8-12 wk C56Bl/6 mice expressed almost exclusively the Exons Q+O-containing form, which is the likely homolog to the previously documented human Y+Z and rat -1+0 forms. In vitro activation using recombinant CD40-ligand and conditioned media from T-helper cells resulted in a 2-to 3-fold elevation of overall ST6Gal I mRNA abundance by Day 3. This coincided with repression of the Q+O form, and appearance of three new isoforms containing 5′-untranslated sequences X 1 , X 2 , or X 3 . The X 1 form persisted through Day 10, when the transition of B cells to plasma cells was completed as evidence by disappearance of CD22 mRNA. In contrast, the X 2 form only transiently appeared at Day 3 and declined to barely detectable levels by Day 7. Expression of the X 3 form, a minor mRNA form, paralleled the X 2 form. The divergent 5′-UT exons are dispersed over 69 kb of linear genomic space of Siat1. Mutually exclusive utilization of these 5′-UT exons in transcripts predicts separate and distinct promoter regulatory regions for each mRNA isoform.