No abstract

Prostaglandin E 2 blocks transforming growth factor TGF ␤1-induced CCN2/CTGF expression in lung and kidney fibroblasts. PGE 2 levels are high in gingival tissues yet CCN2/CTGF expression is elevated in fibrotic gingival overgrowth. Gingival fibroblast expression of CCN2/CTGF in the presence of PGE 2 led us to compare the regulation of CCN2/CTGF expression in fibroblasts cultured from different tissues. Data demonstrate that the TGF␤1-induced expression of CCN2/CTGF in human lung and renal mesangial cells is inhibited by 10 nM PGE 2 , whereas human gingival fibroblasts are resistant. Ten nM PGE 2 increases cAMP accumulation in lung but not gingival fibroblasts, which require 1 M PGE 2 to elevate cAMP. Micromolar PGE 2 only slightly reduces the TGF␤1-stimulated CCN2/CTGF levels in gingival cells. EP2 prostaglandin receptor activation with butaprost blocks the TGF␤1-stimulated expression of CCN2/CTGF expression in lung, but not gingival, fibroblasts. In lung fibroblasts, inhibition of the TGF␤1-stimulated CCN2/CTGF by PGE 2 , butaprost, or forskolin is due to p38, ERK, and JNK MAP kinase inhibition that is cAMP-dependent. Inhibition of any two MAPKs completely blocks CCN2/ CTGF expression stimulated by TGF␤1. These data mimic the inhibitory effects of 10 nM PGE 2 and forskolin that were dependent on PKA activity. In gingival fibroblasts, the sole MAPK mediating the TGF␤1-stimulated CCN2/CTGF expression is JNK. Whereas forskolin reduces TGF␤1-stimulated expression of CCN2/CTGF by 35% and JNK activation in gingival fibroblasts, micromolar PGE 2 -stimulated JNK in gingival fibroblasts and opposes the inhibitory effects of cAMP on CCN2/CTGF expression. Stimulation of the EP3 receptor with sulprostone results in a robust increase in JNK activation in these cells. Taken together, data identify two mechanisms by which TGF␤1-stimulated CCN2/CTGF levels in human gingival fibroblasts resist down-regulation by PGE 2 : (i) cAMP cross-talk with MAPK pathways is limited in gingival fibroblasts; (ii) PGE 2 activation of the EP3 prostanoid receptor stimulates the activation of JNK.

Coronary artery disease results from an inflammatory process in blood vessels of afflicted individuals. This process is accelerated with diabetes for reasons that are largely unknown. Recent evidence indicates that infection at sites remote from the heart leads to bacteremia and endotoxemia, thereby stimulating systemic inflammation, which represents an important risk factor for atherosclerosis. We examined the inflammatory response of the heart/aorta of diabetic db/db mice that develop type II diabetes. Subcutaneous inoculation of lipopolysaccharide was used to mimic a local infection. This stimulated an up-regulation of adhesion molecules, cytokines, and chemokines via an endotoxemia that was significantly more rapid and more pronounced in the diabetic compared with normal mice. The 13- to 30-fold induction of key proinflammatory molecules in the heart/aorta of diabetic mice even exceeded that at the site of inoculation. Given that infection, bacteremia, and endotoxemia are relatively frequent events in humans, these results identify a putative mechanism for increased cardiovascular heart disease in diabetes.