MODULATION OF EXPERIMENTAL MESANGIAL PROLIFERATIVE NEPHRITIS BY INTERFERON-GAMMA

The observation that interferon-gamma (IFN-gamma) inhibits cell prolif eration and collagen synthesis of a variety of cell types in culture h as suggested that IFN-gamma may be useful in the treatment of fibropro liferative diseases. We administered recombinant IFN-gamma subcutaneou sly (10(5) U/kg/day for 3 days) to rats, beginning one day after the i nduction of mesangial proliferative nephritis with anti-Thy 1 antibody . IFN-gamma reduced glomerular (primarily mesangial) cell proliferatio n by 44% at days 2 and 4 compared to vehicle injected control rats wit h anti-Thy 1 nephritis (that is, proliferating cells that excluded the macrophage marker, ED-1, P < 0.001). Despite the inhibition of mesang ial cell proliferation, IFN-gamma did not reduce the overall extracell ular matrix deposition (by silver stain) or deposition of type IV coll agen or laminin (by immunostaining) at 4 or 7 days, and glomerular typ e IV collagen and laminin mRNA levels were increased (1.4 and 1.7-fold ) at 4 days relative to controls. The inability of IFN-gamma treatment to reduce mesangial matrix expansion may relate to the fact that IFN- gamma treated rats had a twofold increase in glomerular macrophages (t hat is, ED-1 positive cells, P < 0.001 at 2 and 4 days) with an increa se in oxidant producing cells (day 2, P < 0.05) and a 1.6-fold increas e in glomerular TGF-beta mRNA expression (4 days). This suggests that the effect of IFN-gamma to inhibit mesangial cell proliferation in glo merulonephritis may be offset by the ability of IFN-gamma to increase glomerular macrophages and TGF-beta expression. These data also show t hat IFN-gamma can partly dissociate the mesangial proliferative respon se from the extracellular matrix expansion in glomerulonephritis.