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

A Schwarting, K Moore, T Wada, G Tesch… - The Journal of …, 1998 - journals.aai.org
A Schwarting, K Moore, T Wada, G Tesch, HJ Yoon, VR Kelley
The Journal of Immunology, 1998journals.aai.org
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 …
Abstract
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.
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