Elevation of serum sialic acid and the ST6Gal-1 sialyltransferase is part of the hepatic system inflammatory response, but the contribution of ST6Gal-1 has remained unclear. Hepatic ST6Gal-1 elevation is mediated by P1, 1 of 6 promoters regulating the ST6Gal1 gene. We report that the P1-ablated mouse, Siat1⌬P1, and a globally ST6Gal-1-deficient mouse had significantly increased peritoneal leukocytosis after intraperitoneal challenge with thioglycollate.
Novel strategies to control the binding of adhesion molecules belonging to the selectin family are required for the treatment of inflammatory diseases. We tested the possibility that synthetic monosaccharide analogs can compete with naturally occurring sugars to alter the O-glycan content on human leukocyte cell surface selectin-ligand, P-selectin glycoprotein ligand-1 (PSGL-1). Resulting reduction in the sialyl Lewis-X-bearing epitopes on this ligand may reduce cell adhesion. Consistent with this hypothesis, 50Mper-acetylated 4F-GalNAc added to the growth media of promyelocytic HL-60 cells reduced the expression of the cutaneous lymphocyte associated-antigen (HECA-452 epitope) by 82% within 2 cell doubling cycles. Cell binding to all 3 selectins (L-, E-, and P-selectin) was reduced in vitro. 4F-GalNAc was metabolically incorporated into PSGL-1, and this was accompanied by an approximately 20% reduction in PSGL-1 glycan content. A 70% to 85% reduction in HECA-452 binding epitope and N-acetyl lactosamine content in PSGL-1 was also noted on 4F-GalNAc addition. Intravenous 4F-GalNAc infusion reduced leukocyte migration to the peritoneum in a murine model of thioglycolate-induced peritonitis. Thus, the compound has pharmacologic activity. Overall, the data suggest that 4F-GalNAc may be applied as a metabolic inhibitor to reduce O-linked glycosylation, sialyl Lewis-X formation, and leukocyte adhesion via the selectins. (Blood. 2010;115:1303-1312) IntroductionThe binding of adhesion molecules belonging to the selectin family to carbohydrate ligands facilitates the adhesion of blood leukocytes to activated endothelial cells, platelets, and other leukocytes in the human vasculature. 1,2 Such molecular interactions play an important role in regulating leukocyte recruitment at sites of inflammation, cancer metastasis, and various cardiovascular disorders. 3 Whereas numerous glycoproteins and glycolipids participate in selectin-mediated cell adhesion, interactions with carbohydrate epitopes expressed on the leukocyte glycoprotein P-selectin glycoprotein ligand-1 (PSGL-1, CD162) are particularly important because this ligand binds all 3 members of the selectin family (E-, P-, and L-selectin) with high affinity and under fluid flow conditions. Structural analysis of the glycans of PSGL-1 expressed on human promyelocytic leukemia HL-60 cells reveals that PSGL-1 is predominantly composed of core-2 based O-linked glycans. 4,5 The prototypic selectin-binding carbohydrate structure sialyl Lewis-X (NeuAc␣2,3Gal1,4(Fuc␣1,3)GlcNAc-, sLe X ; Figure 1A) is expressed on 2% to 14% of these O-glycans.There is active interest in developing antagonists that control/ block selectin-mediated cell adhesion using either competitive inhibitors or metabolic inhibitors. Competitive inhibitors attempt to block cell adhesion by regulating the ligand-binding epitope of either the selectin or its primary counter-receptor PSGL-1. Antagonists used for such inhibition include the tetrasaccharide sLe X and its glycomimetics, 6 humanized antibodies direc...
Cumulative evidence indicates that the sialyltransferase ST6Gal-1 and the sialyl-glycans, which it constructs, are functionally pleiotropic. Expression of the ST6Gal-1 gene is mediated by six distinct promoter/regulatory regions, and we hypothesized that these promoters may be used differentially to produce ST6Gal-1 for different biologic purposes. To examine this hypothesis, we compared a mouse with a complete deficiency in ST6Gal-1 (Siat1 null) with another mouse that we have created previously with a disruption only in the P1 promoter (Siat1DeltaP1). We noted previously greater neutrophilic inflammation associated with ST6Gal-1 deficiency. Here, we report that ST6Gal-1-deficient mice also have significantly elevated eosinophilic responses. Upon i.p. thioglycollate elicitation, eosinophils accounted for over 20% of the total peritoneal inflammatory cell pool in ST6Gal-1-deficient animals, which was threefold greater than in corresponding wild-type animals. A principal feature of allergic respiratory inflammation is pulmonary eosinophilia, we evaluated the role of ST6Gal-1 in allergic lung inflammation. Using OVA and ABPA experimental models of allergic airways, we showed that ST6Gal-1 deficiency led to greater airway inflammation characterized by excessive airway eosinophilia. The severity of airway inflammation was similar between Siat1DeltaP1 and Siat1 null mice, indicating a role for P1-generated ST6Gal-1 in regulating eosinophilic inflammation. Colony-forming assays suggested greater IL-5-dependent eosinophil progenitor numbers in the marrow of ST6Gal-1-deficient animals. Moreover, allergen provocation of wild-type mice led to a significant reduction in P1-mediated ST6Gal-1 mRNA and accompanied decline in circulatory ST6Gal-1 levels. Taken together, the data implicate ST6Gal-1 as a participant in regulating not only Th1 but also Th2 responses, and ST6Gal-1 deficiency can lead to the development of more severe allergic inflammation with excessive eosinophil production.
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