Clusterin is protective in pancreatitis through anti-apoptotic and anti-inflammatory properties.
Clusterin is overexpressed in pancreas during the acute phase of pancreatitis. We intended to clarify the role of clusterin expression in stressed exocrine pancreas. We performed in vitro experiments in transfected AR4-2J cells with modified expression levels of clusterin and in vivo studies in clusterin-deficient mice. AR4-2J cells were exposed to agents mimicking cell-stress during pancreatitis (cerulein, hydrogen peroxide, staurosporine or lysophosphatidylcholine). Clusterin-overexpressing AR4-2J cells showed higher viability after cell stress and accordingly reduced rates of apoptosis and lessened caspase-3 activation. Blockage of endogenous clusterin expression reduced viability and enhanced apoptosis. Presence of clusterin reduced NF-kappaB activation and expression of the NF-kappaB target genes TNF-alpha and MOB-1 under cell stress. Clusterin-deficient mice showed a more severe course of acute experimental pancreatitis with enhanced rates of apoptosis and inflammatory cell infiltration. We concluded that clusterin was protective during inflammation of exocrine pancreas because of its anti-apoptotic and anti-inflammatory functions.
Savković
Vuk
V
Medizinische Klinik und Poliklinik 2, Universitätsklinikum Leipzig AöR, Ph.-Rosenthal-Str. 27, 04103 Leipzig, Germany.
Gantzer
Helen
H
Reiser
Ulrich
U
Selig
Lena
L
Gaiser
Sebastian
S
Sack
Ulrich
U
Klöppel
Günter
G
Mössner
Joachim
J
Keim
Volker
V
Horn
Friedemann
F
Bödeker
Hans
H
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D002108:Ceruletide / Q000494:pharmacology; D051152:Clusterin / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004347:Drug Interactions; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D010195:Pancreatitis / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D014162:Transfection
D000893:Anti-Inflammatory Agents; D051152:Clusterin; D016328:NF-kappa B; D002108:Ceruletide