title: Altered eosinophil profile in mice with ST6Gal-1 deficiency: an additional role for ST6Gal-1 generated by the P1 promoter in regulating allergic inflammation.
abstract: 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.
authors.affiliation: Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York, USA.
authors.forename: Mehrab
authors.initials: M
authors.lastname: Nasirikenari
authors.forename: E V
authors.initials: EV
authors.lastname: Chandrasekaran
authors.forename: Khushi L
authors.initials: KL
authors.lastname: Matta
authors.forename: Brahm H
authors.initials: BH
authors.lastname: Segal
authors.forename: Paul N
authors.initials: PN
authors.lastname: Bogner
authors.forename: Amit A
authors.initials: AA
authors.lastname: Lugade
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Thanavala
authors.forename: James J
authors.initials: JJ
authors.lastname: Lee
authors.forename: Joseph T Y
authors.initials: JT
authors.lastname: Lau
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D001229:Aspergillosis, Allergic Bronchopulmonary / Q000150:complications / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016207:Cytokines / Q000097:blood; D004195:Disease Models, Animal; D004804:Eosinophils / Q000166:cytology / Q000201:enzymology / Q000276:immunology*; D006967:Hypersensitivity / Q000097:blood / Q000150:complications* / Q000201:enzymology / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood; D007958:Leukocyte Count; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008136:Longevity; D051379:Mice; D010538:Peritonitis / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology; D011014:Pneumonia / Q000097:blood / Q000150:complications* / Q000201:enzymology* / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012799:Sialyltransferases / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D013234:Stem Cells; D018418:Th2 Cells / Q000276:immunology; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase
chemical_list: D016207:Cytokines; D007074:Immunoglobulin G; D012799:Sialyltransferases; D000094802:beta-D-Galactoside alpha 2-6-Sialyltransferase