title: Flagellin/Toll-like receptor 5 response was specifically attenuated by keratan sulfate disaccharide via decreased EGFR phosphorylation in normal human bronchial epithelial cells.
abstract: Bacterial or viral infection of the airway plays a critical role in the pathogenesis and exacerbation of chronic obstructive pulmonary disease (COPD) which is expected to be the 3rd leading cause of death by 2020. The induction of inflammatory responses in immune cells as well as airway epithelial cells is observed in the disease process. There is thus a pressing need for the development of new therapeutics. Keratan sulfate (KS) is the major glycosaminoglycans (GAGs) of airway secretions, and is synthesized by epithelial cells on the airway surface. Here we report that a KS disaccharide, [SO3(-)-6]Galβ1-4[SO3(-)-6]GlcNAc, designated as L4, suppressed the production of Interleukin-8 (IL-8) stimulated by flagellin, a Toll-like receptor (TLR) 5 agonist, in normal human bronchial epithelial (NHBE) cells. Such suppressions were not observed by other L4 analogues, N-acetyllactosamine or chondroitin-6-sulfate disaccharide. Moreover, treatment of NHBE cells with L4 inhibited the flagellin-stimulated phosphorylation of epidermal growth factor receptor (EGFR), the down stream signaling pathway of TLRs in NHBE cells. These results suggest that L4 specifically blocks the interaction of flagellin with TLR5 and subsequently suppresses IL-8 production in NHBE cells. Taken together, L4 represents a potential molecule for prevention and treatment of airway inflammatory responses to bacteria infections, which play a critical role in exacerbation of COPD.
authors.affiliation: Systems Glycobiology Research Group, RIKEN-Max Planck Joint Research Center, RIKEN Global Research Cluster, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Shirato
authors.forename: Congxiao
authors.initials: C
authors.lastname: Gao
authors.forename: Fumi
authors.initials: F
authors.lastname: Ota
authors.forename: Takashi
authors.initials: T
authors.lastname: Angata
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Shogomori
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Ohtsubo
authors.forename: Keiichi
authors.initials: K
authors.lastname: Yoshida
authors.forename: Bernd
authors.initials: B
authors.lastname: Lepenies
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Taniguchi
mesh_terms: D001424:Bacterial Infections / Q000150:complications / Q000378:metabolism; D001980:Bronchi / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005408:Flagellin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006801:Humans; D016209:Interleukin-8 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007632:Keratan Sulfate / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051198:Toll-Like Receptor 5 / Q000819:agonists / Q000378:metabolism*
chemical_list: C508606:CXCL8 protein, human; D016209:Interleukin-8; C495346:TLR5 protein, human; D051198:Toll-Like Receptor 5; D005408:Flagellin; D007632:Keratan Sulfate; D066246:ErbB Receptors