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

Kupffer cells (KC) play a central role in the initiation and perpetuation o f hepatic inflammation, which, if uncontrolled, can result in tissue damage , fibrosis, and cirrhosis. Interleukin-10 (IL-10) can inhibit a range of ma crophage 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-1 beta 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 necr osis factor alpha (TNF-alpha) were examined by fluorescent activated cell s orter (FACS), reduction of ferricytochrome C, and bioassay, respectively. R ats were administered intraperitoneal carbon tetrachloride (CCl4), and expr ession of IL-10 mRNA and protein in vivo compared with IL-13 and IL-1 beta by RT-PCR and immunoblotting. Results were correlated with histological inf lammatory changes. Finally, IL-10 gene-deleted (IL-10-/-) mice and wild-typ e (WT) controls were administered intraperitoneal CCl4 biweekly for up to 7 0 days, and the development of inflammation and fibrosis compared by scorin g histological changes. IL-10 mRNA was up-regulated early both in KC in vit ro and in whole liver in vivo, concurrent with that of IL-1 beta. IL-10 was able to inhibit KC production of both SO and TNF-alpha 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 sh owed significantly more severe fibrosis and exhibited higher hepatic TNF-al pha levels than WT controls. These results suggest that IL-10 synthesized d uring the course of liver inflammation and fibrosis may modulate KC actions , and influence subsequent progression of fibrosis.