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 α (TNF‐α), interleukin 2 (IL‐2), IL‐4, and interferon gamma (IFN‐γ) 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 β1 (TGF‐β1), 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.