Biphasic regulation by bile acids of dermal fibroblast proliferation through regulation of cAMP production and COX-2 expression level

Meng J, Ceryak S, Arastu Z, Jones L, Epstein L, Bouscarel B
Source: Am J Physiol Cell Physiol
Publication Date: (2006)
Issue: 291(3): C546-54
Research Area:
Cancer Research/Cell Biology
Cells used in publication:
Fibroblast, dermal (NHDF-Neo), human neonatal
Species: human
Tissue Origin: dermal
Fibroblast, dermal(NHDF-Ad), human adult
Species: human
Tissue Origin: dermal
Nucleofector® I/II/2b
We have previously reported that the bile acids chenodeoxycholate (CDCA), and ursodeoxycholate (UDCA), decreased PGE1-induced cAMP production not only in hepatocytes but also in non-hepatic cells including dermal fibroblasts. In the present study we investigated the physiological relevance of this cAMP modulatory action of bile acids. PGE1 induced cAMP production. PGE1 (1microM), forskolin (1-10microM), and CPT-cAMP (0.1-10microM) decreased fibroblast proliferation in a dose-dependent manner with a maximum inhibition of around 80%. CDCA alone had no significant effect on cell proliferation at a concentration up to 25microM. However, CDCA significantly reduced PGE1-induced cAMP production by 80-90% with an EC50 of ~20microM. Furthermore, at concentrations < 25microM, CDCA significantly attenuated the PGE-1-induced decreased cell proliferation. However, at concentrations of >50microM, while still able to almost completely inhibit PGE-1-induced cAMP production, CDCA, at least in part through increased COX-2 expression and PGE2 synthesis, produced a direct and significant decrease in cell proliferation. This CDCA effect was inhibited by 50-70% by both indomethacin and dexamethasone. In addition, over-expression of COX-2 cDNA Wt resulted in an increased efficacy of CDCA to block cell proliferation. The effects of CDCA on cAMP production and cell proliferation were similar to those of UDCA and under the same conditions cholate had no effect. Results of the present study underline pathophysiological consequences of cholestatic hepatobiliary disorders, in which cells outside of the enterohepatic circulation can be exposed to elevated bile acid concentrations resulting in a potential alteration of the hormonal and cell proliferative response.