The observation that interferon-γ (IFN-γ) inhibits cell proliferation and collagen synthesis of a variety of cell types in culture has suggested that IFN-γ may be useful in the treatment of fibroproliferative diseases. We administered recombinant IFN-γ subcutaneously (105 U/kg/day for 3 days) to rats, beginning one day after the induction of mesangial proliferative nephritis with anti-Thy 1 antibody. IFN-γ reduced glomerular (primarily mesangial) cell proliferation by 44% at days 2 and 4 compared to vehicle injected control rats with anti-Thy 1 nephritis (that is, proliferating cells that excluded the macrophage marker, ED-1, P < 0.001). Despite the inhibition of mesangial cell proliferation, IFN-γ did not reduce the overall extracellular matrix deposition (by silver stain) or deposition of type IV collagen or laminin (by immunostaining) at 4 or 7 days, and glomerular type IV collagen and laminin mRNA levels were increased (1.4 and 1.7-fold) at 4 days relative to controls. The inability of IFN-γ treatment to reduce mesangial matrix expansion may relate to the fact that IFN-γ treated rats had a twofold increase in glomerular macrophages (that is, ED-1 positive cells, P < 0.001 at 2 and 4 days) with an increase in oxidant producing cells (day 2, P < 0.05) and a 1.6-fold increase in glomerular TGF-β mRNA expression (4 days). This suggests that the effect of IFN-γ to inhibit mesangial cell proliferation in glomerulonephritis may be offset by the ability of IFN-γ to increase glomerular macrophages and TGF-β expression. These data also show that IFN-γ can partly dissociate the mesangial proliferative response from the extracellular matrix expansion in glomerulonephritis.
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