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  • Title: Modulation of PPARalpha expression and inflammatory interleukin-6 production by chronic glucose increases monocyte/endothelial adhesion.
    Author: Srinivasan S, Hatley ME, Reilly KB, Danziger EC, Hedrick CC.
    Journal: Arterioscler Thromb Vasc Biol; 2004 May; 24(5):851-7. PubMed ID: 15001458.
    Abstract:
    OBJECTIVE: We have previously reported increased monocyte adhesion to human aortic endothelial cells (HAECs) cultured in 25 mmol/L glucose (HG) compared with normal glucose (NG) (5.5 mmol/L). In this study, we explored mechanisms that contribute to increased monocyte adhesion by elevated glucose. METHODS AND RESULTS: We found that HAECs cultured in HG have increased production of the chemokine interleukin-6 (IL-6). We examined whether IL-6 directly modulated monocyte adhesion to EC. Inhibition of IL-6 using a neutralizing antibody significantly reduced glucose-mediated monocyte adhesion by 50%, and addition of IL-6 directly to human EC stimulated monocyte adhesion. PPARalpha has been reported to negatively regulate expression of IL-6 in vascular cells, so we examined PPARalpha-associated signaling in EC. A known PPARalpha agonist, Wy14,643, prevented glucose-mediated IL-6 production by EC and reduced glucose-mediated monocyte adhesion by 40%. HG-cultured HAEC had a 50% reduction in expression of PPARalpha compared with control EC. Primary aortic EC isolated from PPARalpha knockout (KO) mice showed increased monocyte adhesion compared with EC isolated from control mice. PPARalpha KO EC also had increased production of IL-6. Finally, we measured IL-6 levels in diabetic db/db mice and found significant 6-fold elevations in IL-6 levels in db/db EC. CONCLUSIONS: These data indicate that IL-6 production is increased in diabetes and contributes to early vascular inflammatory changes. PPARalpha protects EC from glucose-mediated monocyte adhesion, in part through regulation of IL-6 production.
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