Increased proinflammatory endothelial response to S100A8/A9 after preactivation through advanced glycation end products.
BACKGROUND
Atherosclerosis is an inflammatory disease in which a perpetuated activation of NFkappaB via the RAGE (receptor for advanced glycation end products)-MAPK signalling pathway may play an important pathogenetic role. As recently S100 proteins have been identified as ligands of RAGE, we sought to determine the effects of the proinflammatory heterodimer of S100A8/S100A9 on the RAGE-NFkappaB mediated induction of proinflammatory gene expression.


METHODS
Human umbilical vein endothelial cells (HUVEC) were preincubated for 72 h with AGE-albumin or unmodified albumin for control, whereas AGE-albumin induction resulted in an upregulation of RAGE. Following this preactivation, cells were stimulated for 48 h with heterodimeric human recombinant S100A8/S100A9.


RESULTS
Heterodimeric S100A8/S100A9 enhanced secretion of IL-6, ICAM-1, VCAM-1 and MCP1 in AGE-albumin pretreated HUVEC in a dose dependent manner. These effects could not be detected after stimulation with the homodimeric proteins S100A8, S100A9, S100A1 and S100B. The effects of heterodimeric S100A8/S100A9 were reduced by inhibition of the MAP-kinase pathways ERK1/2 and p38 by PD 98059 and SB 203580, respectively.


CONCLUSIONS
The heterodimeric S100A8/S100A9 might therefore play a hitherto unknown role in triggering atherosclerosis in diabetes and renal failure, pathophysiological entities associated with a high AGE burden. Thus, blocking heterodimeric S100A8/S100A9 might represent a novel therapeutic modality in treating atherosclerosis.
Ehlermann
Philipp
P
Universität Heidelberg, Abteilung Innere Medizin III, Heidelberg, Germany. philipp.ehlermann@med.uni-heidelberg.de
Eggers
Kai
K
Bierhaus
Angelika
A
Most
Patrick
P
Weichenhan
Dieter
D
Greten
Johannes
J
Nawroth
Peter P
PP
Katus
Hugo A
HA
Remppis
Andrew
A
D040501:Calgranulin A / Q000502:physiology*; D040502:Calgranulin B / Q000494:pharmacology / Q000502:physiology*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins; D014471:Umbilical Veins; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
C111835:CCL2 protein, human; D040501:Calgranulin A; D040502:Calgranulin B; D018932:Chemokine CCL2; D017127:Glycation End Products, Advanced; D015850:Interleukin-6; D011994:Recombinant Proteins; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D020928:Mitogen-Activated Protein Kinases