TNF-alpha enhances colony-stimulating factor-1-induced macrophage accumulation in autoimmune renal disease

• Published in: The Journal of immunology (1950) Vol. 157; no. 1; pp. 427 - 432
• Main Authors: Moore, KJ, Yeh, K, Naito, T, Kelley, VR
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01-07-1996
• Subjects: Adjuvants, Immunologic - pharmacology; Animals; Bone Marrow - immunology; Bone Marrow - metabolism; Cell Division - drug effects; Cell Division - immunology; Colony-Forming Units Assay; Epithelium - pathology; Female; Gene Transfer Techniques; Kidney Glomerulus - pathology; Kidney Tubules - pathology; Lupus Nephritis - genetics; Lupus Nephritis - immunology; Lupus Nephritis - pathology; Macrophage Colony-Stimulating Factor - biosynthesis; Macrophage Colony-Stimulating Factor - genetics; Macrophage Colony-Stimulating Factor - pharmacology; Macrophages - drug effects; Macrophages - pathology; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Mutant Strains; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.157.1.427

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.