Repeated concanavalin A challenge in mice induces an interleukin 10-producing phenotype and liver fibrosis.
Weekly injections of Concanavalin A (Con A) were performed in BALB/c mice to evaluate the pattern of cytokine production and liver injury. High serum levels of tumor necrosis factor alpha (TNF-alpha), interleukin 2 (IL-2), IL-4, and interferon gamma (IFN-gamma) were found in the serum after the first 2 injections of Con A but rapidly decreased from the third injection. Conversely, IL-10 serum levels after repeated Con A challenge increased by 7 times from week 1 to 20. In vivo depletion studies indicated that CD4(+) T cells are essential in IL-10 production. Hepatocyte necrosis was only observed after the first injections of Con A whereas centrilobular inflammatory infiltrates persisted up to 20 weeks. Perisinusoidal liver fibrosis was also increasingly detected in BALB/c mice, whereas no fibrous change was observed in nude mice after 6 weeks of Con A challenge. The number of stellate cells, detected by immunostaining, increased after 20 weeks of Con A injections. Liver cytokine messenger RNA (mRNA) expression after 20 weeks showed expression of transforming growth factor beta1 (TGF-beta1), IL-10, and IL-4 whereas IL-2 was no more expressed. The present study shows that mice repeatedly injected with Con A develop liver fibrosis. The cytokine-release pattern observed after 1 injection of Con A is rapidly shifted towards an immunomodulatory phenotype characterized by the systemic production of large amounts of IL-10.
Louis
H
H
Laboratories of Experimental Gastroenterology, Faculty of Medicine, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium.
Le Moine
A
A
Quertinmont
E
E
Peny
M O
MO
Geerts
A
A
Goldman
M
M
Le Moine
O
O
Devière
J
J
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology; D003208:Concanavalin A / Q000008:administration & dosage* / Q000494:pharmacology; D004334:Drug Administration Schedule; D005260:Female; D016753:Interleukin-10 / Q000096:biosynthesis*; D008099:Liver / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced* / Q000401:mortality; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis; D010641:Phenotype; D013997:Time Factors
D003208:Concanavalin A; D016753:Interleukin-10