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

We have previously reported that the bile acids chenodeoxycholate (CDCA) and ursodeoxycholate (UDCA) decreased PGE1-induced cAMP production in a time- and dose-dependent manner not only in hepatocytes but also in nonhepatic 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 in a time- and dose-dependent manner. Moreover, PGE1 (1 microM), forskolin (1-10 microM), and the membrane-permeable cAMP analog CPT-cAMP (0.1-10 microM) decreased dermal fibroblast proliferation in a dose-dependent manner with a maximum inhibition of approximately 80%. CDCA alone had no significant effect on cell proliferation at a concentration up to 25 microM. However, CDCA significantly reduced PGE1-induced cAMP production by 80-90% with an EC(50) of approximately 20 microM. Furthermore, at concentrations < or =25 microM, CDCA significantly attenuated the PGE-1-induced decreased cell proliferation. However, at concentrations of 50 microM and above, while still able to almost completely inhibit PGE-1-induced cAMP production, CDCA, at least in part through an increased cyclooxygenase-2 (COX-2) expression level and PGE2 synthesis, produced a direct and significant decrease in cell proliferation. Indeed, the CDCA effect was partially blocked by approximately 50-70% by both indomethacin and dexamethasone. In addition, overexpression of COX-2 cDNA wild type resulted in an increased efficacy of CDCA to block cell proliferation. The effects of CDCA on both 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. Under these conditions, low bile acid concentrations can attenuate the negative hormonal control on cell proliferation, resulting in the stimulation of cell growth, while at high concentrations these bile acids provide for a profound and prolonged inhibition of cell proliferation.