Advanced glycation end products (AGEs) activate mast cells
Article first published online: 2 JUN 2010
© 2010 The Authors. British Journal of Pharmacology © 2010 The British Pharmacological Society
British Journal of Pharmacology
Volume 161, Issue 2, pages 442–455, September 2010
How to Cite
Sick, E., Brehin, S., André, P., Coupin, G., Landry, Y., Takeda, K. and Gies, J. (2010), Advanced glycation end products (AGEs) activate mast cells. British Journal of Pharmacology, 161: 442–455. doi: 10.1111/j.1476-5381.2010.00905.x
- Issue published online: 23 AUG 2010
- Article first published online: 2 JUN 2010
- Received 12 March 2010Accepted19 April 2010
- mast cells;
BACKGROUND AND PURPOSE Advanced glycation endproducts (AGEs) represent one of the many types of chemical modifications that occur with age in long-lived proteins. AGEs also accumulate in pathologies such as diabetes, cardiovascular diseases, neurodegeneration and cancer. Mast cells are major effectors of acute inflammatory responses that also contribute to the progression of chronic diseases. Here we investigated interactions between AGEs and mast cells.
EXPERIMENTAL APPROACHES Histamine secretion from AGEs-stimulated mast cells was measured. Involvement of a receptor for AGEs, RAGE, was assessed by PCR, immunostaining and use of inhibitors of RAGE. Production of reactive oxygen species (ROS) and cytokines was measured.
KEY RESULTS Advanced glycation endproducts dose-dependently induced mast cell exocytosis with maximal effects being obtained within 20 s. RAGE mRNA was detected and intact cells were immunostained by a specific anti-RAGE monoclonal antibody. AGEs-induced exocytosis was inhibited by an anti-RAGE antibody and by low molecular weight heparin, a known RAGE antagonist. RAGE expression levels were unaltered after 3 h treatment with AGEs. AGE-RAGE signalling in mast cells involves Pertussis toxin-sensitive Gi-proteins and intracellular Ca2+ increases as pretreatment with Pertussis toxin, caffeine, 2-APB and BAPTA-AM inhibited AGE-induced exocytosis. AGEs also rapidly stimulated ROS production. After 6 h treatment with AGEs, the pattern of cytokine secretion was unaltered compared with controls.
CONCLUSIONS AND IMPLICATIONS Advanced glycation endproducts activated mast cells and may contribute to a vicious cycle involving generation of ROS, increased formation of AGEs, activation of RAGE and to the increased low-grade inflammation typical of chronic diseases.