title: IFN-gamma limits macrophage expansion in MRL-Fas(lpr) autoimmune interstitial nephritis: a negative regulatory pathway.
abstract: 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 (Mphi) growth factors (CSF-1-TEC, GM-CSF-1-TEC) and infused under the renal capsule. To determine the impact of IFN-gamma in Mphi growth factor-incited renal injury, we constructed a MRL-Fas(lpr) IFN-gamma-receptor (IFN-gammaR)-deficient strain. Gene transfer of CSF-1 or GM-CSF incited more severe interstitial nephritis in IFN-gammaR-deficient than in IFN-gammaR-intact MRL-Fas(lpr) mice, consisting of an increase of Mphi. To determine the mechanism responsible for the increase in Mphi in IFN-gammaR-deficient MRL-Fas(lpr) mice, we evaluated Mphi proliferation, apoptosis, and recruitment. Proliferation of bone marrow Mphi from IFN-gammaR-intact MRL-Fas(lpr) costimulated with CSF-1 or GM-CSF and IFN-gamma was reduced twofold, while the IFN-gammaR-deficient MRL-Fas(lpr) bone marrow Mphi remained stable. Furthermore, we detected more proliferating and fewer apoptotic Mphi within the interstitium in IFN-gammaR-deficient MRL-Fas(lpr) mice. Using unilateral ureteral ligation we established that IFN-gammaR signaling does not alter Mphi recruitment into the kidney. Thus, the increase in Mphi elicited by Mphi growth factors in IFN-gammaR-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 Mphi-mediated renal inflammation.
authors.affiliation: Laboratory of Autoimmune Disease, Renal Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: A
authors.initials: A
authors.lastname: Schwarting
authors.forename: K
authors.initials: K
authors.lastname: Moore
authors.forename: T
authors.initials: T
authors.lastname: Wada
authors.forename: G
authors.initials: G
authors.lastname: Tesch
authors.forename: H J
authors.initials: HJ
authors.lastname: Yoon
authors.forename: V R
authors.initials: VR
authors.lastname: Kelley
mesh_terms: D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D004195:Disease Models, Animal; D005260:Female; D018014:Gene Transfer Techniques; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000502:physiology; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007668:Kidney / Q000276:immunology / Q000473:pathology; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000502:physiology; D008264:Macrophages / Q000276:immunology* / Q000473:pathology*; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D017471:Receptors, Interferon / Q000502:physiology; D015398:Signal Transduction; D000096743:Interferon gamma Receptor
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D016173:Macrophage Colony-Stimulating Factor; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor