Received for publication June 6, 2007.
Revised September 13, 2007.
Accepted for publication September 14, 2007.

ADENOSINE A_2A RECEPTOR OCCUPANCY STIMULATES COLLAGEN EXPRESSION BY HEPATIC STELLATE CELLS VIA PATHWAYS INVOLVING PKA, SRC AND ERK 1/2 SIGNALING CASCADE OR P38 MAPK SIGNALING PATHWAY

Abstract

Prior studies indicate that adenosine and the adenosine A_2A receptor play a role in hepatic fibrosis by a mechanism which has been proposed to involve direct stimulation of hepatic stellate cells (HSCs). The objective of this study was to determine whether primary hepatic stellate cells produce collagen in response to adenosine (via activation of adenosine A_2A receptors) and to further determine the signaling mechanisms involved in adenosine A_2A receptor-mediated promotion of collagen production. Cultured primary hepatic stellate cells increase their collagen production following stimulation of the adenosine A_2A receptor in a dose-dependent fashion. Similarly, LX-2 cells, a human hepatic stellate cell line, increases expression of precollagen I and precollagen III mRNA and their translational proteins, collagen type I and type III in response to pharmacologic stimulation of adenosine A_2A receptors. Based on the use of pharmacologic inhibitors of signal transduction, adenosine A_2A receptor-mediated stimulation of precollagen I mRNA and collagen type I collagen expression were regulated by signal transduction involving protein kinase A, Src and MEK/ERK but surprisingly adenosine A_2A receptor-mediated stimulation of precollagen III mRNA and collagen type III protein expression depend upon activation of p38 MAPK, findings confirmed by siRNA-mediated knockdown of Src, ERK1, ERK2 and p38 MAPK. These results indicate that adenosine A_2A receptors signal for increased collagen production by multiple signaling pathways. These results provide strong evidence in support of the hypothesis that adenosine receptors promote hepatic fibrosis, at least in part, via direct stimulation of collagen expression and that signaling for collagen production proceeds via multiple pathways.

Key words: Adenosine, Gs family, Protein Kinase A, Protein Kinases (other)

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