N(epsilon)-carboxymethyllysine-modified proteins are unable to bind to RAGE and activate an inflammatory response.
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.
Buetler
Timo M
TM
Nestlé Research Center, Lausanne, Switzerland. Timo.Buetler@rdls.nestle.com
Leclerc
Estelle
E
Baumeyer
Alexandra
A
Latado
Helia
H
Newell
John
J
Adolfsson
Oskar
O
Parisod
Véronique
V
Richoz
Janique
J
Maurer
Sarah
S
Foata
Francis
F
Piguet
Dominique
D
Junod
Sylviane
S
Heizmann
Claus W
CW
Delatour
Thierry
T
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
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