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

Abstract

-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 dosedependent manner. Moreover, PGE1 (1 M), forskolin (1-10 M), and the membrane-permeable cAMP analog CPT-cAMP (0.1-10 M) decreased dermal fibroblast proliferation in a dose-dependent manner with a maximum inhibition of ϳ80%. CDCA alone had no significant effect on cell proliferation at a concentration up to 25 M. However, CDCA significantly reduced PGE1-induced cAMP production by 80 -90% with an EC50 of ϳ20 M. Furthermore, at concentrations Յ25 M, CDCA significantly attenuated the PGE-1-induced decreased cell proliferation. However, at concentrations of 50 M 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 ϳ50 -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. chenodeoxycholic acid; cyclic adenosine monophosphate cAMP, which can be induced by the prostaglandins (PG) PGE1 and PGE2, is known to have both proliferative and antiproliferative effects, according to cell type. For example, cAMP stimulates the proliferation of cells, such as hepatocytes and 3T3 cells, while inhibiting the proliferation of normal human skin fibroblasts, gastric cells, and hepatic stellate cells (20,30,38,55). The PGE2 is also a potent inhibitor of fibroblast migration, proliferation and collagen synthesis (23,24,54). PGs are derived from arachidonic acid through the cyclooxygenase (COX)

Bile Acid Administration Elicits an Intestinal Antimicrobial Program and Reduces the Bacterial Burden in Two Mouse Models of Enteric Infection

“…Extrapolation of data from cancer studies (40)(41)(42)(43)(44)(45) suggested the possibility that a CDCA-Wnt/␤-catenin or a CDCA-COX2-Wnt/␤-catenin pathway might function in the healthy intestinal epithelium and drive AMPP synthesis. Expression of Ptgs2 (Cox2) in the ileum was in fact upregulated by CDCA feeding (Fig.…”

Bile acid stimulates hepatocyte polarization through a cAMP-Epac-MEK-LKB1-AMPK pathway

“…Activation of adenylate cyclase by bile acids increases cellular cAMP in many cells (21)(22)(23); however, whether this occurs in hepatocytes is unknown. Because taurocholate-accelerated canalicular network formation is adenylate cyclase-dependent ( Fig.…”

Differential effects of prostaglandin E2 and enamel matrix derivative on the proliferation of human gingival and dermal fibroblasts and gingival keratinocytes

“…In contrast, we found that dermal fibroblasts are less sensitive to the antimitogenic effect of PGE 2 than gingival fibroblasts. Prostaglandin E 2 inhibits proliferation of many cell types, including fibroblasts from various sources (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18), and in several of these cells it was shown to operate via the EP 2 receptor and cAMP generation (10,12,14,(16)(17)(18). Like GFs (48), DFs express all four EP receptors (49) and, since PGE 2 causes cAMP production in DFs (50), it is reasonably safe to assume that EP 2 also mediates the inhibitory effect of PGE 2 on DF proliferation.…”

“…However, exaggerated local production of PGs due to trauma or infection of the wound may interfere with proper cutaneous healing. In addition to its recognized role in the inflammation per se , PGE 2 has documented antiproliferative effects on gingival (7–10) and dermal fibroblasts (11,12) as well as on fibroblasts from other sources [tendon (13), lung (14), embryonic (15) and liver (16)] and on other cell types, such as gastric carcinoma cells (17) and arterial smooth muscle cells (18). Interestingly, there are no solid data on whether PGE 2 affects the proliferation of gingival epithelial cells (keratinocytes).…”