Interleukin‐10 expression and function in experimental murine liver inflammation and fibrosis

Kupffer cells (KC) play a central role in the initiation and perpetuation of hepatic inflammation, which, if uncontrolled, can result in tissue damage, fibrosis, and cirrhosis. Interleukin‐10 (IL‐10) can inhibit a range of macrophage functions. We hypothesized that the transcription, synthesis, and release of IL‐10 may influence the development of liver injury. Rat KC were activated in vitro with lipopolysaccharide (LPS), and expression of IL‐10 mRNA compared with IL‐13 and IL‐1β by reverse‐transcription polymerase chain reaction (RT‐PCR). The effects of pretreatment with recombinant IL‐10 (rIL‐10) on KC phagocytosis, production of superoxide (SO), and tumor necrosis factor α (TNF‐α) were examined by fluorescent activated cell sorter (FACS), reduction of ferricytochrome C, and bioassay, respectively. Rats were administered intraperitoneal carbon tetrachloride (CCl4), and expression of IL‐10 mRNA and protein in vivo compared with IL‐13 and IL‐1β by RT‐PCR and immunoblotting. Results were correlated with histological inflammatory changes. Finally, IL‐10 gene‐deleted (IL‐10−/−) mice and wild‐type (WT) controls were administered intraperitoneal CCl4 biweekly for up to 70 days, and the development of inflammation and fibrosis compared by scoring histological changes. IL‐10 mRNA was up‐regulated early, both in KC in vitro and in whole liver in vivo, concurrent with that of IL‐1β. IL‐10 was able to inhibit KC production of both SO and TNF‐α in vitro, and this was achieved more effectively than IL‐4 or IL‐13; no such effects were seen on KC phagocytosis. After 70 days of treatment with CCl4, IL‐10−/− mice showed significantly more severe fibrosis and exhibited higher hepatic TNF‐α levels than WT controls. These results suggest that IL‐10 synthesized during the course of liver inflammation and fibrosis may modulate KC actions, and influence subsequent progression of fibrosis.