Hepatic acute phase induction of murine  -galactoside  2,6 sialyltransferase (ST6Gal I) is IL-6 dependent and mediated by elevation of Exon H--containing class of transcripts

Abstract

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.

Role for Hepatic and Circulatory ST6Gal-1 Sialyltransferase in Regulating Myelopoiesis

“…Suppressed circulatory ST6Gal-1 also accompanies other conditions that require elevated production of inflammatory cells, such as during bacterial and thioglycollate-induced peritonitis (5,22), or during recovery from cyclophosphamide-induced myelosuppression. 3 Taken together, the data strongly indicate a role for extrinsically produced ST6Gal-1, e.g. those originating from the liver, in the regulation of bone marrow hematopoietic events.…”

“…Mutant mice unable to express ST6Gal-1 are essentially devoid of ␣2,6-sialyl modifications, as evidenced by the lack of binding to the Sambucus nigra lectin (SNA) 2 that specifically recognizes these structures (1). Hepatic expression of ST6Gal-1 is principally driven by P1 (2,3), one of six independently operative promoter regions regulating transcription of the ST6Gal-1 gene (4). Another promoter, P3, is responsible for low-level ST6Gal-1 expression in the liver (5).…”

Remodeling of Marrow Hematopoietic Stem and Progenitor Cells by Non-self ST6Gal-1 Sialyltransferase

“…Rather, HSPC ␣2,6-sialylation is dependent on distally produced non-self ST6Gal-1. Early work has documented that extracellular, circulatory ST6Gal-1 is governed by glucocorticoids and interleukins such as IL-6 (37,38). Acute local inflammation is also accompanied by depression of circulatory ST6Gal-1 presumably to allow increased production of inflammatory cells (10).…”

Differential Expression of β-Galactoside α2,6 Sialyltransferase and Sialoglycans in Normal and Cirrhotic Liver and Hepatocellular Carcinoma

“…ST6Gal I expression is induced as part of the acute phase response (Dalziel et al, 1999). Despite its importance for liver metabolism, our knowledge about the synthesis and expression of sialyltransferases and the respective sialoglycans in various liver diseases, in particular human hepatocellular carcinomas (HCC), is still sparse.…”