**4.2 Inflammatory signaling mediated by RAGE**

Ligand engagement of RAGE leads to prolonged inflammation, resulting in a RAGEdependent expression of proinflammatory mediators such as monocyte chemoattractant protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) 79, 80. RAGE-mediated proinflammatory signals could potentially converge with insulin signaling system (Figure 2). The engagement of RAGE has been reported to induce activation of the transcription factor nuclear factor-κB (NF-κB). Recent reports by Harja et al demonstrate that RAGE mediates upregulation of VCAM-1 in response to S100b and oxLDL and JNK MAP kinase underlies the RAGE ligand-stimulated molecular events 81. It is not known at present whether this is also the case in classical insulin target cells. JNK activity is strikingly increased in critical metabolic sites (eg. adipose and liver tissues) 82, and is shown to be crucial in IRS-1 phosphorylation and consequently insulin resistance 82, 83. Moreover, the main pathological consequence of RAGE ligation is the induction of intracellular reactive oxygen species (ROS) via NAD(P)H oxidases and other identified mechanisms such as mitochondrial electron transport chain 84, which consequently results in oxidative stress in the cells 85. Oxidative stress is emerging as a feature of obesity and an important factor in the development of insulin resistance 86, 87. Both the NF-kB and JNK pathways can be activated under the conditions of oxidative stress, and this may be important for the ability of ROS to mediate insulin resistance. RAGE has a short cytosolic portion that contains 43 amino acids 72. So far, adaptors and/or scaffold proteins that interact with the cytosolic tail of RAGE has barely been identified. The RAGE mutant lacking the 43-residue C-terminal tail fails to activate NF-κB, and expression of the mutant receptor results in a dominant negative effect against RAGE-mediated production of proinflammatory cytokines from macrophages 56, 57.

Fig. 2. RAGE and insulin signaling. RAGE is known to activate JNK pathway, which could phosphorylate serine-residue of insulin receptor substrate (IRS) and inhibit its activity. RAGE mediated generation of reactive oxygen spices (ROS) may alternatively influence insulin signaing.
