Impaired selectin-ligand biosynthesis and reduced inflammatory responses in β-1,4-galactosyltransferdse-I-deficient mice

Selectins recognize ligands containing carbohydrate chains such as sialyl Lewis x (sLe(x)) that are mainly presented at the terminus of N-acetyl lactosamine repeats on core 2 O-glycans. Several glycosyltransferases act successively to extend the N-acetyl lactosamine repeats and to synthesize sLe(x), and beta-1,4-galactosyltransferase (beta4GaIT) plays a key role in these processes. Recently isolated 6 beta4GaIT genes are candidates, but their individual roles, including those in selectin-ligand biosynthesis, remain to be elucidated. More than 80% of the core 2 O-glycans on the leukocyte membrane glycoproteins of beta4GaIT-I-deficient mice lacked galactose residues in beta-1,4 linkage, and soluble. P-selectin binding to neutrophils and monocytes of these mice was significantly reduced, indicating an impairment of selectin-ligand biosynthesis. beta4GaIT-I-deficient mice exhibited blood leukocytosis but normal lymphocyte homing to peripheral lymph nodes. Acute and chronic inflammatory responses, including the contact hypersensitivity (CHS) and delayed-type hypersensivity (DTH) responses, were suppressed, and neutrophil infiltration into inflammatory sites was largely reduced in these mice. Our results demonstrate that beta4GaIT-I is a major galactosyltransferase responsible for selectin-ligand biosynthesis and that inflammatory responses of beta4GaIT-I-deficient mice are impaired because of the defect in selectin-ligand biosynthesis.