IFN-γ limits macrophage expansion in MRL-Faslpr autoimmune interstitial nephritis:: A negative regulatory pathway

IFN-gamma is capable of enhancing and limiting inflammation, Therefore, an increase in IFN-gamma in autoimmune, MRL-Fas(lpr) mice could exacerbate or thwart renal injury, We have established a retroviral gene transfer approach to incite interstitial nephritis in MRL-Fas(lpr) mice that is rapid, enduring, and circumscribed, Renal tubular epithelial cells (TEC) were genetically modified to secrete macrophage (M phi) growth factors (CSF-1-TEC, GM-CSF-1-TEC) and infused under the renal capsule, To determine the impact of IFN-gamma in M phi growth factor-incited renal injury, we constructed a MRL-Fas(lpr) IFN-gamma-receptor (IFN-gamma R)-deficient strain, Gene transfer of CSF-1 or GM-CSF incited more severe interstitial nephritis in IFN-gamma R-deficient than in IFN-gamma R-intact MRL-Fas(lpr) mice, consisting of an increase of M phi. To determine the mechanism responsible for the increase in M phi, in IFN-gamma R-deficient MRL-Fas(lpr) mice, we evaluated M phi proliferation, apoptosis, and recruitment, Proliferation of bone marrow M phi from IFN-gamma R-intact MRL-Fas(lpr) costimulated with CSF-1 or GM-CSF and IFN-gamma was reduced twofold, while the IFN-gamma R-deficient MRL-Fas(lpr) bone marrow M alpha remained stable, Furthermore, we detected more proliferating and fewer apoptotic M phi within the interstitium in IFN-gamma R-deficient MRL-Fas(lpr) mice. Using unilateral ureteral ligation we established that IFN-gamma R signaling does not alter M phi recruitment into the kidney, Thus, the increase in M phi elicited by M phi growth factors in IFN-gamma R-deficient MRL-Fas(lpr) mice is a result of enhanced proliferation and decreased apoptosis, and is independent of recruitment, Taken together, we suggest that IFN-gamma provides a negative regulatory pathway capable of limiting M phi-mediated renal inflammation.