TY - JOUR
T1 - Interleukin-10 expression and function in experimental murine liver inflammation and fibrosis
AU - Thompson, Kerry
AU - Maltby, Julia
AU - Fallowfield, Jon
AU - Mcaulay, Martin
AU - Millward-Sadler, Harry
AU - Sheron, Nick
PY - 1998
Y1 - 1998
N2 - 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 (CC14), 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 (IL10-/-) mice and wild-type (WT) controls were administered intraperitoneal CC14 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 CC14, 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.
AB - 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 (CC14), 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 (IL10-/-) mice and wild-type (WT) controls were administered intraperitoneal CC14 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 CC14, 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.
UR - http://www.scopus.com/inward/record.url?scp=0031769883&partnerID=8YFLogxK
U2 - 10.1002/hep.510280620
DO - 10.1002/hep.510280620
M3 - Article
C2 - 9828224
AN - SCOPUS:0031769883
SN - 0270-9139
VL - 28
SP - 1597
EP - 1606
JO - Hepatology
JF - Hepatology
IS - 6
ER -