Endogenous interleukin-10 modulates fibrosis and regeneration in experimental chronic pancreatitis.
Interleukin (IL)-10, a potent anti-inflammatory cytokine, limits the severity of acute pancreatitis and downregulates transforming growth factor (TGF)-beta release by inflammatory cells on stimulation. Proinflammatory mediators, reactive oxygen species, and TGF-beta can activate pancreatic stellate cells and their synthesis of collagen I and III. This study evaluates the role of endogenous IL-10 in the modulation of the regeneration phase following acute pancreatitis and in the development of pancreatic fibrosis. IL-10 knockout (KO) mice and their C57BL/6 controls were submitted to repeated courses (3/wk, during 6 wk, followed by 1 wk of recovery) of cerulein-induced acute pancreatitis. TGF-beta(1) release was measured on plasma, and its pancreatic expression was assessed by quantitative RT-PCR and immunohistochemistry. Intrapancreatic IL-10 gene expression was assessed by semiquantitative RT-PCR, and intrapancreatic collagen content was assessed by picrosirius staining. Activated stellate cells were detected by immunohistochemistry. S phase intrapancreatic cells were marked using tritiated thymidine labeling. After repeated acute pancreatitis, IL-10 KO mice had more severe histological lesions and fibrosis (intrapancreatic collagen content) than controls. TGF-beta(1) plasma levels, intrapancreatic transcription, and expression by ductal and interstitial cells, as well as the number of activated stellate cells, were significantly higher. IL-10 KO mice disclosed significantly fewer acinar cells in S phase, whereas the opposite was observed for pseudotubular cells. Endogenous IL-10 controls the regeneration phase and limits the severity of fibrosis and glandular atrophy induced by repeated episodes of acute pancreatitis in mice.
Demols
Anne
A
Department of Gastroenterology, Hôpital Erasme and Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, B 1070 Brussels, Belgium. ademols@ulb.ac.be
Van Laethem
Jean-Luc
JL
Quertinmont
Eric
E
Degraef
Chantal
C
Delhaye
Myriam
M
Geerts
Albert
A
Deviere
Jacques
J
D000208:Acute Disease; D000818:Animals; D001284:Atrophy; D002455:Cell Division / Q000276:immunology; D002908:Chronic Disease; D003094:Collagen / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology; D005355:Fibrosis; D015870:Gene Expression / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010179:Pancreas / Q000473:pathology / Q000502:physiology; D010195:Pancreatitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D012008:Recurrence; D012038:Regeneration / Q000276:immunology*; D014158:Transcription, Genetic / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1
C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10; D003094:Collagen