Vitamin A inhibits pancreatic stellate cell activation: implications for treatment of pancreatic fibrosis

Joshua A McCarroll ¹, Phoebe A Phillips ¹, Nicole Santucci ¹, Romano C Pirola ¹, Jeremy Wilson ¹ and Minoti Apte ^1*

¹ Pancreatic Research Group, University of New South Wales, Sydney, Australia

^* To whom correspondence should be addressed. E-mail: m.apte{at}unsw.edu.au.

Accepted 31 May 2005

Abstract

Background & Aims: Activated pancreatic stellate cells (PSCs) are implicated in the production of alcohol- induced pancreatic fibrosis. PSC activation is invariably associated with a loss of the cytoplasmic vitamin A (retinol) stores. Furthermore, retinol and ethanol are known to be metabolised by similar pathways. Our group and others have demonstrated that ethanol-induced PSC activation is mediated by the mitogen-activated protein kinase (MAPK) pathway, but the specific role of retinol and its metabolites all-trans retinoic acid (ATRA) and 9- cis retinoic acid (9-RA) in PSC quiescence/activation, or its influence on ethanol-induced PSC activation is not known. Therefore, the aims of this study were to i) examine the effects of retinol, ATRA and 9-RA on PSC activation; ii) determine whether retinol, ATRA and 9-RA influence MAPK signalling in PSCs; and iii) assess the effect of retinol supplementation on PSCs activated by ethanol.

Methods: Cultured rat PSCs were incubated with retinol, ATRA or 9-RA for varying time periods and assessed for: i) proliferation; ii) expression of & [alpha]-smooth muscle actin (a-SMA), collagen I, fibronectin and laminin; and iii) activation of MAPKs (ERK1/2, p38 kinase and JNK). The effect of retinol on PSCs treated with ethanol was also examined by incubating cells with ethanol in the presence or absence of retinol for 5 days, followed by assessment of -SMA, collagen I, fibronectin and laminin expression.

Results: Retinol, ATRA and 9-RA significantly inhibited: (i) cell proliferation, (ii) expression of & [alpha]-SMA, collagen I, fibronectin and laminin, and iii) activation of all 3 classes of MAPKs. Furthermore, retinol prevented ethanol-induced PSC activation as indicated by inhibition of the ethanol-induced increase in -SMA, collagen I, fibronectin and laminin expression.

Conclusions: Retinol and its metabolites ATRA and 9-RA induce quiescence in culture-activated PSCs associated with a significant decrease in the activation of all 3 classes of MAPKs in PSCs. Ethanol-induced PSC activation is prevented by retinol supplementation.

Keywords: mitogen-activated protein kinases, pancreatic fibrosis, pancreatic stellate cells, vitamin A

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