title: N(epsilon)-carboxymethyllysine-modified proteins are unable to bind to RAGE and activate an inflammatory response.
abstract: Advanced glycation endproducts (AGEs) containing carboxymethyllysine (CML) modifications are generally thought to be ligands of the receptor for AGEs, RAGEs. It has been argued that this results in the activation of pro-inflammatory pathways and diseases. However, it has not been shown conclusively that a CML-modified protein can interact directly with RAGE. Here, we have analyzed whether beta-lactoglobulin (bLG) or human serum albumin (HSA) modified chemically to contain only CML (10-40% lysine modification) can (i) interact with RAGE in vitro and (ii) interact with and activate RAGE in lung epithelial cells. Our results show that CML-modified bLG or HSA are unable to bind to RAGE in a cell-free assay system (Biacore). Furthermore, they are unable to activate pro-inflammatory signaling in the cellular system. Thus, CML probably does not form the necessary structure(s) to interact with RAGE and activate an inflammatory signaling cascade in RAGE-expressing cells.
authors.affiliation: Nestlé Research Center, Lausanne, Switzerland. Timo.Buetler@rdls.nestle.com
authors.forename: Timo M
authors.initials: TM
authors.lastname: Buetler
authors.forename: Estelle
authors.initials: E
authors.lastname: Leclerc
authors.forename: Alexandra
authors.initials: A
authors.lastname: Baumeyer
authors.forename: Helia
authors.initials: H
authors.lastname: Latado
authors.forename: John
authors.initials: J
authors.lastname: Newell
authors.forename: Oskar
authors.initials: O
authors.lastname: Adolfsson
authors.forename: Véronique
authors.initials: V
authors.lastname: Parisod
authors.forename: Janique
authors.initials: J
authors.lastname: Richoz
authors.forename: Sarah
authors.initials: S
authors.lastname: Maurer
authors.forename: Francis
authors.initials: F
authors.lastname: Foata
authors.forename: Dominique
authors.initials: D
authors.lastname: Piguet
authors.forename: Sylviane
authors.initials: S
authors.lastname: Junod
authors.forename: Claus W
authors.initials: CW
authors.lastname: Heizmann
authors.forename: Thierry
authors.initials: T
authors.lastname: Delatour
mesh_terms: D002460:Cell Line; D004847:Epithelial Cells; D015870:Gene Expression / Q000187:drug effects; D005982:Glutathione Transferase / Q000276:immunology / Q000378:metabolism; D006031:Glycosylation; D006038:Glyoxylates / Q000737:chemistry; D006801:Humans; D007249:Inflammation / Q000209:etiology* / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D007782:Lactoglobulins / Q000737:chemistry / Q000378:metabolism*; D008239:Lysine / Q000031:analogs & derivatives* / Q000737:chemistry; D012333:RNA, Messenger / Q000032:analysis; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D006038:Glyoxylates; D015850:Interleukin-6; D016209:Interleukin-8; D007782:Lactoglobulins; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D012709:Serum Albumin; D014409:Tumor Necrosis Factor-alpha; C048496:N(6)-carboxymethyllysine; D005982:Glutathione Transferase; C031150:glyoxylic acid; D008239:Lysine