N(epsilon)-carboxymethyllysine-modified proteins are unable to bind to RAGE and activate an inflammatory response

Mol Nutr Food Res. 2008 Mar;52(3):370-8. doi: 10.1002/mnfr.200700101.


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.

MeSH terms

  • Cell Line
  • Epithelial Cells
  • Gene Expression / drug effects
  • Glutathione Transferase / immunology
  • Glutathione Transferase / metabolism
  • Glycosylation
  • Glyoxylates / chemistry
  • Humans
  • Inflammation / etiology*
  • Inflammation / genetics
  • Interleukin-6 / genetics
  • Interleukin-8 / genetics
  • Lactoglobulins / chemistry
  • Lactoglobulins / metabolism*
  • Lysine / analogs & derivatives*
  • Lysine / chemistry
  • RNA, Messenger / analysis
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • Serum Albumin / chemistry
  • Serum Albumin / metabolism*
  • Tumor Necrosis Factor-alpha / genetics


  • Glyoxylates
  • Interleukin-6
  • Interleukin-8
  • Lactoglobulins
  • RNA, Messenger
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • Serum Albumin
  • Tumor Necrosis Factor-alpha
  • N(6)-carboxymethyllysine
  • Glutathione Transferase
  • glyoxylic acid
  • Lysine