title: A novel function for a glucose analog of blood group H antigen as a mediator of leukocyte-endothelial adhesion via intracellular adhesion molecule 1.
abstract: The 4A11 antigen is a unique cytokine-inducible antigen up-regulated on rheumatoid arthritis synovial endothelium compared with normal endothelium. In soluble form, this antigen, Lewisy-6/H-5-2 (Ley/H), or its glucose analog, 2-fucosyllactose (H-2g), mediates angiogenesis. The Ley/H antigen is structurally related to the soluble E-selectin ligand, sialyl Lewisx, and is selectively expressed in skin, lymphoid organs, thymus, and synovium, suggesting that it may be important in leukocyte homing or adhesion. In the present study, we used H-2g as a functional substitute to demonstrate a novel property for Ley/H antigen in inducing leukocyte-endothelial adhesion. H-2g significantly enhanced the expression of human dermal microvascular endothelial cells (HMVECs) intercellular adhesion molecule-1 (ICAM-1), but not vascular cell adhesion molecule-1, E-selectin, and P-selectin. Immunoprecipitation and Western blotting showed glycolipids Ley-6, H-5-2, or the glucose analog H-2g quickly activated human microvascular endothelial cell line-1 (HMEC-1) Janus kinase 2 (JAK2) and that the JAK2 inhibitor, AG-490, completely inhibited HMVEC ICAM-1 expression and HL-60 adhesion to HMEC-1s. Use of a JAK/signal transducer and activator of transcription (STAT) profiling system confirmed that H-2g selectively activated STAT3 but not STAT1 and STAT2. AG-490 inhibited H-2g-induced Erk1/2 and PI3K-Akt activation, suggesting that JAK2 is upstream of the Erk1/2 and PI3K-Akt pathways. Furthermore, the JAK2 inhibitor AG-490, the Erk1/2 inhibitor PD98059, or the phosphatidylinositol 3-kinase inhibitor LY294002 or antisense oligodeoxynucleotides directed against JAK2, Erk1/2, or phosphatidylinositol 3-kinase blocked H-2g-induced HMVEC ICAM-1 expression and HL-60 adhesion to HMEC-1s. Hence, H-2g signals through JAK2 and its downstream signal transducers STAT3, Erk1/2, and phosphatidylinositol 3-kinase result in ICAM-1 expression and cell adhesion. Potential treatment strategies through the inhibition of JAK-dependent pathways to target H-2g signals may provide a useful approach in inflammation-driven diseases like rheumatoid arthritis.
authors.affiliation: Department of Medicine, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Avenue, Chicago, IL 60611, USA.
authors.forename: Kui
authors.initials: K
authors.lastname: Zhu
authors.forename: M Asif
authors.initials: MA
authors.lastname: Amin
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kim
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Katschke
authors.forename: Christy C
authors.initials: CC
authors.lastname: Park
authors.forename: Alisa E
authors.initials: AE
authors.lastname: Koch
mesh_terms: D000017:ABO Blood-Group System / Q000276:immunology*; D021581:Active Transport, Cell Nucleus; D015153:Blotting, Western; D002448:Cell Adhesion; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D017930:Genes, Reporter; D005947:Glucose / Q000737:chemistry*; D018922:HL-60 Cells; D006801:Humans; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D053614:Janus Kinase 2; D007962:Leukocytes / Q000166:cytology*; D008024:Ligands; D008156:Luciferases / Q000378:metabolism; D008833:Microcirculation; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D015398:Signal Transduction; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D000017:ABO Blood-Group System; D004791:Enzyme Inhibitors; D008024:Ligands; D011518:Proto-Oncogene Proteins; D018799:Intercellular Adhesion Molecule-1; D008156:Luciferases; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D005947:Glucose