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.