IFN-GAMMA RECEPTOR SIGNALING IS ESSENTIAL FOR THE INITIATION, ACCELERATION, AND DESTRUCTION OF AUTOIMMUNE KIDNEY-DISEASE IN MRL-FAS(LPR) MICE

CSF-1 and TNF-alpha in the kidney of MRL-Fas(lpr) mice are proximal ev ents that precede and promote autoimmune lupus nephritis, while apopto sis of renal parenchymal cells is a feature of advanced human lupus ne phritis. In the MRL-Fas(lpr) kidney, infiltrating T cells that secrete IFN-gamma are a hallmark of disease. To examine the impact of IFN-gam ma on renal injury in MRL-Fas(lpr) mice, we constructed a IFN-gamma R- deficient strain. In MRL-Fas(lpr) mice lacking IFN-gamma R, circulatin g and intrarenal CSF-I were absent, TNF-alpha was markedly reduced, su rvival was extended, lymphadenopathy and splenomegaly were prevented, and the kidneys remained protected from destruction. Mesangial cells ( MC) that were signaled through the IFN-gamma R induced CSF-1 and TNF-a lpha in MRL-Fas(lpr) mice. We detected a large number of apoptotic ren al parenchymal cells in advanced nephritis and determined that signali ng via the IFN-gamma R induces apoptosis of tubular epithelial cells ( TEC), hut not MC. By comparison, TNF-alpha induces apoptosis in MC, bu t not TEC, of the MRL-Fas(lpr) strain. Thus, IFN-gamma is directly and indirectly responsible for apoptosis of TEC and MC in MRL-Fas(lpr) mi ce, respectively, In conclusion IFN-gamma R signaling is essential for the initiation (CSF-1), acceleration (CSF-1 and TNF-alpha), and apopt otic destruction of renal parenchymal cells in MRL-Fas(lpr) autoimmune kidney disease.