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-1โค 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 โฃ (TNF-โฃ) were examined by fluorescent activated cell sorter (FACS), reduction of ferricytochrome C, and bioassay, respectively. Rats were administered intraperitoneal carbon tetrachloride (CCl 4 ), and expression of IL-10 mRNA and protein in vivo compared with IL-13 and IL-1โค by RT-PCR and immunoblotting. Results were correlated with histological inflammatory changes. Finally, IL-10 gene-deleted (IL-10ุ/ุ) mice and wild-type (WT) controls were administered intraperitoneal CCl 4 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-1โค. IL-10 was able to inhibit KC production of both SO and TNF-โฃ 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 CCl 4 , IL-10ุ/ุ mice showed significantly more severe fibrosis and exhibited higher hepatic TNF-โฃ levels than WT controls. These results suggest that IL-10 synthe-sized during the course of liver inflammation and fibrosis may modulate KC actions, and influence subsequent progres-