PANCREATITIS

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

J A McCarroll, P A Phillips, N Santucci, R C Pirola, J S Wilson, M V Apte

Pancreatic Research Group, Department of Gastroenterology, Liverpool Hospital, Australia, and University of New South Wales, Sydney, Australia

Correspondence to:
Dr M Apte
Pancreatic Research Group, Room 463, Level 4, Health Services Building, Liverpool Hospital, Campbell Street, Liverpool, NSW 2170, Australia; m.apte{at}unsw.edu.au

Background and aims: Activated pancreatic stellate cells (PSCs) are implicated in the production of alcohol induced pancreatic fibrosis. PSC activation is invariably associated with loss of 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 smooth muscle actin (-SMA), collagen I, fibronectin, and laminin; and (iii) activation of MAPKs (extracellular regulated kinases 1 and 2, p38 kinase, and c-Jun N terminal kinase). 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 five 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 -SMA, collagen I, fibronectin, and laminin, and (iii) activation of all three 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 three classes of MAPKs in PSCs. Ethanol induced PSC activation is prevented by retinol supplementation.

Abbreviations: ADH, alcohol dehydrogenase; ATRA, all-trans retinoic acid; ECL, enhanced chemiluminescence; ERK1/2, extracellular regulated kinases 1 and 2; HSCs, hepatic stellate cells; IMDM, Iscove’s modified Dulbecco’s medium; JNK, c-Jun N terminal kinase; MAPK, mitogen activated protein kinase; MKP-1, mitogen activated phosphatase 1; PSCs, pancreatic stellate cells; RALDH, retinaldehyde dehydrogenase; RAR, retinoic acid receptor; RXR, retinoid X receptor; RolDH, retinol dehydrogenase; Rol, retinol; 9-RA, 9-cis retinoic acid; RT-PCR, reverse transcriptase-polymerase chain reaction; -SMA, smooth muscle actin; SV, sodium orthovanadate

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

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