Expression of fas antigen may be a unique macrophage function of Kupffer cells

Fas antigen has been implicated in mediating apoptosis, i.e., programmed ce ll death. Fas antigen expression has been found on various cell types, but not on spleen or bone marrow macrophages in mice. An insertional mutation i n the structural fas gene has been identified in mice with the lymphoprolif erative (lpr) mutation. We postulate that the fas antigen mutation in lpr m ice results in decreased KC apoptosis and subsequent KC dysfunction. Kupffer cells were isolated from BALB/c, MRL-+/+ and MRL-lpr/lpr mice and a nalyzed for fas antigen expression by two-color flow cytometry with antibod ies specific to macrophage marker Moma-2 and mouse fas antigen. Kupffer cel ls from BALB/c mice showed double positive cells after 24 hours in culture, with maximum fas antigen expression at 36 hours. Kupffer cells from MRL-+/ + mice also stained positive for fas antigen expression at 36 hours of cult ure. No fas antigen was detected on MRL-lpr/lpr KC at 36 hours of culture. Addition of 100 U/ml IFN-gamma to the culture did nor induce expression of fas on KC from MRL-lpr/lpr mice but increased fas expression two to three f old on KC from MRL-+/+ and BALB/c mice. The failure of fas anti gen express ion on KC of MRL mice carrying the lpr mutation suggested a possible defect in apoptosis. Apoptosis was demonstrated in MRL-+/+ but not lpr/lpr KC by DNA fragmentation. Histological studies using macrophage-specific antibody F4/80 showed a 52% increase in KC number in MRL-lpr/lpr mice in comparison to KC from MRL-+/+ and BALB/c mice. The numbers of F4/80 positive splenic m acrophages were not significantly different in the above three strains. The se results demonstrate that normal mouse KC are unique macrophages in expre ssing fas antigen. Our data suggest that failure of fas expression on KC as sociated with the lpr mutation may result in abnormal KC apoptosis with an increase in their liver sinusoidal presence. These results may contribute t o understanding the rapid repopulating of donor KC during bone marrow trans plantation.