The inhibition of DNA synthesis by prostaglandin E₂ in human gingival fibroblasts is independent of the cyclic AMP‐protein kinase A signal transduction pathway

Abstract

In this study we attempted to clarify the mechanism of the inhibitory effects of PGE2 on DNA synthesis in Gin‐1 (fibroblasts derived from healthy human gingiva) from the aspect of the cyclic AMP‐dependent protein kinase signal transduction pathway. PGE2 upregulated intracellular cyclic AMP accumulation and inhibited DNA synthesis in Gin‐1 in a dose‐dependent manner. When the PGE2‐induced intracellular cyclic AMP accumulation was further enhanced by treatment with the cyclic AMP‐phosphodiesterase inhibitor, IBMX, the inhibitory effect of PGE2 on DNA synthesis was also enhanced. Furthermore, when we examined the effects of forskolin, an activator of cyclic AMP production, on intracellular cyclic AMP accumulation and DNA synthesis, similar results were obtained. However, inhibitors of cyclic AMP‐dependent protein kinase (protein kinase A) such as HA1004 did not diminish the inhibitory effect of PGE2 on DNA synthesis in Gin‐1. These results suggest that in Gin‐I, PGE2‐induced cyclic AMP accumulation may not lead to the activation of protein kinase A or protein kinase A activity may not relate directly to the growth inhibitory effect of PGE2, and that PGE2 does not inhibit DNA synthesis through the cyclic AMP‐protein kinase A signal transduction pathway in Gin‐1.

Prostaglandin E2 inhibits the proliferation of human gingival fibroblasts via the EP2 receptor and Epac

“…These data are in agreement with those of Arai [1998], who used a GF-cell line, as well as other studies in which PGE 2 inhibits the proliferation of other fibroblasts [Hsi and Eling, 1998;Koide et al, 2004;Liu et al, 2004;Huang et al, 2007] via cAMP production. Out of the four E-type prostanoid receptors, two use cAMP as secondary messenger: EP 2 and EP 4 .…”

“…This finding is in line with other reports of anti-proliferative effects of PGE 2 on fibroblasts from a variety of sources and other cell types. In terms of gingival fibroblasts, these data corroborate and extend those of Arai et al [1995Arai et al [ , 1998, who used a GF cell line, to primary human GFs. This is the first report to elucidate some of the mechanisms whereby PGE 2 inhibits GF proliferation.…”

“…In contrast, cAMP inhibition of the proliferation of retinal pigmented epithelial cells [Hecquet et al, 2002] or smooth muscle cells [Kassel et al, 2008] is PKA-independent. In terms of gingival fibroblasts, the only previously existing data were that the antimitogenic effect of PGE 2 on a GF cell line was not abrogated by HA1004, a PKA antagonist [Arai et al, 1998]. In agreement with these observations, we were unable to block the anti-mitogenic Fig.…”

“…Among the prostanoids found in inflamed gingiva, prostaglandin E 2 (PGE 2 ) has documented anti-proliferative effects in tendon [Thampatty et al, 2006], lung [Huang et al, 2007], embryonic [Hsi and Eling, 1998], hepatic [Koide et al, 2004], and gingival [Arai et al, 1995[Arai et al, , 1998 fibroblasts as well as other cell types.…”

C2-ceramide inhibits the prostaglandin E2-induced accumulation of cAMP in human gingival fibroblasts

“…Activation of the EP3 receptor reduces or increases cAMP levels by activating inhibitory G (G i ) or stimulatory G (G s ) proteins depending on the particular splice variant expressed by the cell (15). In human gingival fibroblasts, PGE 2 inhibited the DNA synthesis and proliferation (1,37), and downregulated intercellular adhesion molecule-1 expression by cAMP-dependent signaling pathways (24). Therefore, cAMP is thought to be the main intracellular second messenger for response to PGE 2 , and is the crucial modulator of the functional activity of inflammation.…”