IFN-γ limits macrophage expansion in MRL-Fas(lpr) autoimmune interstitial nephritis: A negative regulatory pathway

Andreas Schwarting, Kathryn Moore, Takashi Wada, Gregory Tesch, Hyung Jin Yoon, Vicki Rubin Kelley

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IFN-γ is capable of enhancing and limiting inflammation. Therefore, an increase in IFN-γ 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 (Mφ) growth factors (CSF-1-TEC, GM-CSF-1- TEC) and infused under the renal caPSule. To determine the impact of IFN-γ in Mφ growth factor-incited renal injury, we constructed a MRL-Fas(lpr) IFN- γ-receptor (IFN-γR)-deficient strain. Gene transfer of CSF-1 or GM-CSF incited more severe interstitial nephritis in IFN-γR-deficient than in IFN- γR-intact MRL-Fas(lpr) mice, consisting of an increase of Mφ. To determine the mechanism responsible for the increase in Mφ in IFN-γR-deficient MRL- Fas(lpr) mice, we evaluated Mφ proliferation, apoptosis, and recruitment. Proliferation of bone marrow Mφ from IFN-γR-intact MRL-Fas(lpr) costimulated with CSF-1 or GM-CSF and IFN-γ was reduced twofold, while the IFN-γR-deficient MRL-Fas(lpr) bone marrow Mφ remained stable. Furthermore, we detected more proliferating and fewer apoptotic Mφ within the interstitium in IFN-γR-deficient MRL-Fas(lpr) mice. Using unilateral ureteral ligation we established that IFN-γR signaling does not alter Mφ recruitment into the kidney. Thus, the increase in Mφ elicited by Mφ growth factors in IFN-γR-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-γ provides a negative regulatory pathway capable of limiting Mφ-mediated renal inflammation.

Original languageEnglish
Pages (from-to)4074-4081
Number of pages8
JournalJournal of Immunology
Issue number8
Publication statusPublished - 15 Apr 1998
Externally publishedYes

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