Modulation of experimental mesangial proliferative nephritis by interferon-gamma.
The observation that interferon-gamma (IFN-gamma) inhibits cell proliferation and collagen synthesis of a variety of cell types in culture has suggested that IFN-gamma may be useful in the treatment of fibroproliferative diseases. We administered recombinant IFN-gamma subcutaneously (10(5) U/kg/day for 3 days) to rats, beginning one day after the induction of mesangial proliferative nephritis with anti-Thy 1 antibody. IFN-gamma 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-gamma 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-gamma treatment to reduce mesangial matrix expansion may relate to the fact that IFN-gamma 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-beta mRNA expression (4 days). This suggests that the effect of IFN-gamma to inhibit mesangial cell proliferation in glomerulonephritis may be offset by the ability of IFN-gamma to increase glomerular macrophages and TGF-beta expression. These data also show that IFN-gamma can partly dissociate the mesangial proliferative response from the extracellular matrix expansion in glomerulonephritis.
Johnson
R J
RJ
Division of Nephrology, University of Washington Medical Center, Seattle, USA.
Lombardi
D
D
Eng
E
E
Gordon
K
K
Alpers
C E
CE
Pritzl
P
P
Floege
J
J
Young
B
B
Pippin
J
J
Couser
W G
WG
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D005109:Extracellular Matrix / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005920:Glomerular Mesangium / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015432:Glomerulonephritis, Membranoproliferative / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D007124:Immunoenzyme Techniques; D007371:Interferon-gamma / Q000494:pharmacology*; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D018800:Thy-1 Antigens; D016212:Transforming Growth Factor beta / Q000378:metabolism
D016326:Extracellular Matrix Proteins; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D011994:Recombinant Proteins; D018800:Thy-1 Antigens; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma