HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 291/2/G275    most recent 00346.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Le, M. Articles by Bouscarel, B. Search for Related Content PubMed PubMed Citation Articles by Le, M. Articles by Bouscarel, B.

LIVER AND BILIARY TRACT

Bile acids stimulate PKC autophosphorylation and activation: role in the attenuation of prostaglandin E₁-induced cAMP production in human dermal fibroblasts

Gastroenterology Research Laboratory, Departments of ¹Medicine, ²Biochemistry and Molecular Biology, and ³Pharmacology and Physiology, George Washington University Medical Center, Washington, District of Columbia

Submitted 26 July 2005 ; accepted in final form 2 March 2006

The aim was to identify the specific PKC isoform(s) and their mechanism of activation responsible for the modulation of cAMP production by bile acids in human dermal fibroblasts. Stimulation of fibroblasts with 25–100 µM of chenodeoxycholic acid (CDCA) and ursodeoxycholic acid (UDCA) led to YFP-PKC and YFP-PKC translocation in 30–60 min followed by a transient 24- to 48-h downregulation of the total PKC, PKC, and PKC protein expression by 30–50%, without affecting that of PKC. Increased plasma membrane translocation of PKC was associated with an increased PKC phosphorylation, whereas increased PKC translocation to the perinuclear domain was associated with an increased accumulation of phospho-PKC Thr505 and Tyr311 in the nucleus. The PKC specificity on the attenuation of cAMP production by CDCA was demonstrated with PKC downregulation or inhibition, as well as PKC isoform dominant-negative mutants. Under these same conditions, neither phosphatidylinositol 3-kinase, p38 MAP kinase, p42/44 MAP kinase, nor PKA inhibitors had any significant effect on the CDCA-induced cAMP production attenuation. CDCA concentrations as low as 10 µM stimulated PKC autophosphorylation in vitro. This bile acid effect required phosphatidylserine and was completely abolished by the presence of Gö6976. CDCA at concentrations less than 50 µM enhanced the PKC activation induced by PMA, whereas greater CDCA concentrations reduced the PMA-induced PKC activation. CDCA alone did not affect PKC activity in vitro. In conclusion, although CDCA and UDCA activate different PKC isoforms, PKC plays a major role in the bile acid-induced inhibition of cAMP synthesis in fibroblasts. This study emphasizes potential consequences of increased systemic bile acid concentrations and cellular bile acid accumulation in extrahepatic tissues during cholestatic liver diseases.

ursodeoxycholic acid; chenodeoxycholic acid; taurocholic acid