Downregulation of lipopolysaccharide-induced intercellular adhesion molecule-1 expression via EP2/EP4 receptors by prostaglandin E2 in human fibroblasts.

Q2 · MEDICINE

Article

Author: Ishikawa, I. ; Murota, S. ; Noguchi, K. ; Shitashige, M. ; Iwasaki, K. ; Izumi, Y. ; Umeda, M.

In the present study, the effect of prostaglandin E2 (PGE2) on intercellular adhesion molecule-1 (ICAM-1) expression in human gingival fibroblasts (HGF) stimulated with lipopolysaccharides (LPS) was investigated. LPS were isolated from periodontopathic bacteria, Actinobacillus actinomycetemcomitans (A. actinomycetemcomitans) and Porphyromonas gingivalis (P. gingivalis), by the phenol-water method and Escherichia coli (E. coli) LPS was used as a control. PGE2 significantly inhibited A. actinomycetemcomitans-, P. gingivalis- and E. coli-LPS-induced ICAM-1 expression. Next, of four PGE2 receptor subtypes (EP1, EP2, EP3 and EP4), we examined which subtype(s) was involved in inhibition of LPS-elicited ICAM-1 expression by PGE2. Eleven-deoxy-PGE1, a selective EP2/EP4 agonist, and butaprost, a selective EP2 agonist, attenuated A. actinomycetemcomitans-, P. gingivalis- and E. coli-LPS-elicited ICAM-1 expression, although butaprost was less potent than PGE2 and 11-deoxy-PGE1. Sulprostone, an EP1/EP3 agonist, and ONO-AP-324, an EP3 agonist, was inert to the LPS-elicited ICAM-1 expression. Furthermore, dibutyryl cAMP, a cAMP analogue, and forskolin, an adenylate cyclase activator, downregulated A. actinomycetemcomitans-, P. gingivalis- and E. coli-LPS-elicited ICAM-1 expression in HGF. Our data suggest that PGE2 downregulates A. actinomycetemcomitans- and P. gingivalis-LPS-induced ICAM-1 expression in HGF, via EP2/EP4 receptors by cAMP-dependent signaling pathways. The cAMP-elevating agents such as EP2/EP4 receptor activators may serve to control inflammatory and immune responses in periodontal disease.

01 Jan 1999·InflammationQ2 · MEDICINE

Prostaglandin E2 downregulates interferon-gamma-induced intercellular adhesion molecule-1 expression via EP2 receptors in human gingival fibroblasts.

Q2 · MEDICINE

Article

Author: Murato, S. ; Noguchi, K. ; Shitashige, M. ; Iwasaki, K. ; Ishikawa, I.

In the present study, the effect of prostaglandin E2 (PGE2) on intercellular adhesion molecule-1 (ICAM-1) expression in interferon-gamma (IFN-gamma)-stimulated human gingival fibroblasts (HGF) was investigated. Addition of PGE2 to HGF inhibited ICAM-1 expression elicited by IFN-gamma. As PGE2 elevated intercellular cyclic AMP (cAMP) levels in HGF in a dose-dependent fashion, the effect of dibutyryl cAMP and 8-bromo-cAMP, cAMP analogues, on IFN-gamma-elicited ICAM-1 expression was examined. Both the agents downregulated ICAM-1 expression in IFN-gamma-stimulated HGF. Next, we examined which subtype(s) of the four PGE2 receptor subtypes (EP1, EP2, EP3 and EP4) modulated the ICAM-1 expression elicited by IFN-gamma, using subtype-specific agonists or antagonists. An EP2/EP4 agonist, 11-deoxy-PGE1, attenuated IFN-gamma-elicited ICAM-1 expression in a concentration-dependent manner. A specific EP4 antagonist, AH-23848B, showed no effect on inhibition of IFN-gamma-elicited ICAM-1 expression by PGE2 and 11-deoxy-PGE1. Butaprost, an EP2-selective agonist, mimicked inhibition of IFN-gamma-elicited ICAM-1 expression by 11-deoxy-PGE1. An EP3 agonist, ONO-AP-324, was inert with respect to IFN-gamma-elicited ICAM-1 expression. Sulprostone, an EP1/EP3 agonist, showed stimulatory effect on ICAM-1 expression elicited by IFN-gamma. From these results, we suggest that PGE2 downregulates IFN-gamma-induced ICAM-1 expression in HGF, primarily via EP2 receptors by cAMP-dependent signaling pathways.

01 Nov 1996·Journal of Cellular PhysiologyQ2 · BIOLOGY

Positive and negative regulation of cell proliferation through prostaglandin receptors in NIH-3T3 cells

Q2 · BIOLOGY

Article

Author: Yoshiaki Hashimoto ; Kiyoshi Kurokawa ; Shigeo Taniguchi ; Masako Togoh ; Hiroaki Satoh ; Tsuyoshi Watanabe

Among major eicosanoids and their analogs, prostaglandin (PG) F2 alpha > PGD2 > PGE1 > or = PGE2 > iloprost, a stable agonist of PGI2, dose-dependently stimulated DNA synthesis in quiescent NIH-3T3 cells. PGF2 alpha, PGD2, and PGE2, in that order, formed inositol phosphates and elevated intracellular Ca2+ ([Ca2+]i) but did not form cAMP nor inhibit forskolin-induced cAMP formation. Iloprost, PGI2, and PGE1 induced cAMP formation dose dependently with an ED50 of around 10(-7) M, and PGE2 at more than 10(-6) M did it. [3H]PGF2 alpha and [3H]PGD2 bindings membranes from NIH-3T3 cells were displaced in the order of PGF2 alpha > PGD2 > or = PGE2, while [3H]PGE2 binding was displaced by PGE2 > PGD2 > or = PGF2 alpha. Expression of mRNA encoding EP1 and EP4 (EP2) subtypes could be detected by reverse transcription- polymerase chain reaction using primers specific for EP1 and EP4 (EP2) cDNAs, but not that of EP3 subtype mRNA. The dose dependence of cAMP formation on iloprost and PGI2 and that of [Ca2+]i elevation on PGF2 alpha, D2, and E2 were similar to that of [3H]thymidine incorporation on the corresponding agonists. Fluprostenol (1 microM), a PGF2 alpha receptor agonist > 17-phenyl-trinor-PGE2 (1 microM), an EP1 receptor agonist stimulated [3H]thymidine incorporation, but an EP3 receptor agonist, ONO-AP-324 nor an EP4 (EP2) receptor agonist, 11-deoxy-PGE1 (1 microM) did not. Iloprost, dibutyryl cAMP, forskolin, or cholera toxin, when applied alone, enhanced [3H]thymidine incorporation, while they inhibited [3H]thymidine incorporation induced by submaximal concentrations of PGF2 alpha or epidermal growth factor (EGF), when applied within 12 hr after agonist stimulation. These results suggest that the proliferation of NIH-3T3 cells is stimulated by PGs via the PGF2 alpha receptor, EP1 subtype of PGE receptor, and the PGI2/PGE1 receptor through [Ca2+]i- and cAMP-dependent pathways, and that cAMP pathway negatively cross-talks with [Ca2+]i-or receptor tyrosine kinase-mediated DNA synthesis in a cell cycle-dependent manner.

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Indication	Highest Phase	Country/Location	Organization	Date
Stomach Ulcer	Discovery	JP	Ono Pharmaceutical Co., Ltd.	-

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