High Glucose Enhances Interleukin-6-induced Vascular Endothelial Growth Factor 165 Expression via Activation of Gp130-mediated p44/42 MAPK-CCAAT/Enhancer Binding Protein Signaling in Gingival Fibroblasts

Abstract

Diabetic patients are susceptible to severe inflammatory periodontitis manifesting as swollen gingiva with bleeding, but the underlying mechanism is not well understood. Our purpose was to determine the effect of a high glucose (HG) condition on the interleukin-6/soluble interleukin-6 receptor (IL-6/sIL-6R)-induced activation of signaling and vascular endothelial growth factor (VEGF) expression in human gingival fibroblasts (HGFs). In this study, HGFs were cultured for at least two passages under a normal glucose (NG; 5.5 mM) condition or high glucose (25 mM) condition. Importantly, the HG condition significantly induced expression of gp130 mRNA in HGFs compared with levels in control cells. Consistent with the expression of its mRNA, the HG condition also increased the expression of gp130 protein, and phosphorylation of the tyrosine residue by gp130 was enhanced significantly by IL-6/sIL-6R stimulation. Furthermore, the HG condition enhanced the IL-6/sIL-6R-induced phosphorylation of p44/42 MAPK and led to subsequent activation of CCAAT/enhancer binding protein in nuclei. In contrast, there was no significant difference in phosphorylation of JNK between the HG and NG condition. Interestingly, HGFs increased IL-6/sIL-6R-induced VEGF165 mRNA expression and VEGF165 secretion under the HG condition compared with levels under the NG condition. In contrast, the induction of VEGF165 secretion was partially inhibited by PD98059 (selective p44/42 MAPK inhibitor) under the HG condition. In addition, the VEGF165 secretion was completely inhibited by the combination of PD98059 and SP600125 (JNK inhibitor). Our findings suggest that the HG condition indirectly increases VEGF expression via activation of gp130-mediated p44/42 MAPK-CCAAT/enhancer binding protein signaling in HGFs. Thus, elevated VEGF secretion in HGFs under the HG condition may play a role in the development of the severe periodontitis observed in diabetic patients.

Amino Acid Residues Required for Physical and Cooperative Transcriptional Interaction of STAT3 and AP-1 Proteins c-Jun and c-Fos

“…One important role of this phosphorylation is removal of the inhibitor histone deacetylase 3 (29). Moreover IL-6 has been reported to activate some mitogenactivated protein kinase pathways capable of phosphorylating c-Jun in certain cell types (13,22). We found that c-Jun S63,S73 phosphorylation occurs in HepG2 cells in response to IL-6 plus the soluble IL-6 receptor in a dose-dependent manner (Fig.…”

Vascular Endothelial Growth Factor Blockade Reduces Plasma Cytokines in a Murine Model of Polymicrobial Sepsis

“…The mechanism by which VEGF regulates C/EBPβ remains unclear. However, in a recent article human gingival fibroblast when exposed to hyperglycemia, had demonstrated IL-6 induced phosphorylation of p44/p42 MAPK with subsequent CEBP nuclear translocation and VEGF 165 expression (24).…”

High Glucose-Mediated Cytokine Regulation in Gingival Fibroblasts and THP-1 Macrophage: a Possible Mechanism of Severe Periodontitis with Diabetes

“…Furthermore, vascular endotherial growth factor (VEGF) is a significant factor for diabetic complications, and is implicated in the development of neovascularization and endotherial dysfunction in diabetic retinopathy [13]. We showed that HG enhances IL-6/sIL-6R-induced VEGF production in HGFs [14]. A series of reports suggest that exaggerated response of HGF affected by both elevated glucose and inflammatory cytokines may lead to severe periodontitis.…”