title: TNF-alpha enhances colony-stimulating factor-1-induced macrophage accumulation in autoimmune renal disease.
abstract: The lpr mutation on the MRL background accelerates autoimmune nephritis in which macrophage (M phi) accumulation is prominent. Renal disease is absent in other strains with lpr. TNF-alpha and CSF-1 are increased in the kidney of MRL-lpr mice with loss of renal function. We have established that CSF-1 can incite renal injury in mice with the lpr mutation, and M phi from the MRL strain hyper-respond to this growth factor. We hypothesized that TNF-alpha enhanced the M phi response to CSF-1 in MRL-lpr mice. We now report that TNF-alpha enhanced CSF-1-induced bone marrow M phi proliferation in MRL-lpr mice, and not in congenic MRL +/+, normal C3H +/+, and BALB/c, or another strain with lpr (C3H-lpr). Using a gene transfer approach to deliver CSF-1 together with TNF-alpha into the kidney, we evaluated the impact on renal injury. Tubular epithelial cells genetically modified to produce CSF-1 (CSF-1-TEC) and TNF-alpha (TNF-TEC) placed under the renal capsule caused a greater accumulation of M phi in the implant site than CSF-1-TECs alone in MRL-lpr, but not MRL +/+ mice. We noted in tissues adjacent but not distal to the implanted TECs, an increase in M phi in the interstitium and surrounding glomeruli of MRL-lpr but not MRL +/+ mice. This indicated that CSF-1 and TNF-alpha released by TECs were responsible for promoting renal pathology. Taken together, these data suggest that the simultaneous expression of TNF-alpha and CSF-1 in the MRL-lpr kidney fosters M phi accumulation. We speculate that the increase in M phi in the kidney in response to CSF-1 and TNF-alpha is responsible for the rapid tempo of autoimmune renal injury in MRL-lpr mice.
authors.affiliation: Immunogenetics and Transplantation, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: Moore
authors.forename: K
authors.initials: K
authors.lastname: Yeh
authors.forename: T
authors.initials: T
authors.lastname: Naito
authors.forename: V R
authors.initials: VR
authors.lastname: Kelley
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D001853:Bone Marrow / Q000276:immunology / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D003114:Colony-Forming Units Assay; D004848:Epithelium / Q000473:pathology; D005260:Female; D018014:Gene Transfer Techniques; D007678:Kidney Glomerulus / Q000473:pathology; D007684:Kidney Tubules / Q000473:pathology; D008181:Lupus Nephritis / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D016173:Macrophage Colony-Stimulating Factor / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*
chemical_list: D000276:Adjuvants, Immunologic; D014409:Tumor Necrosis Factor-alpha; D016173:Macrophage Colony-Stimulating Factor