The broad objective of this proposal is to examine the relationship between autoimmune mediated renal injury and the activation of cytokine genes in invading macrophages (macs) in the kidney and intrinsic renal cells. We plan to dissect the kinetic and functional relationship between these events. Cellular and molecular approaches will be used to examine two spontaneous murine models of autoimmune lupus nephritis, the MRL-lpr and NZBxNZW F1 hybrid mice . Renal injury will be determined morphologically, immunohistochemically and functionally. Gene expression for cytokines will be analyzed by Northern blots and quantitated by laser densitometry and cytokine production detected by bioassays and radioimmunassays. Analysis will extend from the whole kidney to isolated compartments including cortex, medulla, glomeruli and cultured and transformed glomerular macs and mesangial cells. Using in-situ hybridization techniques cytokine mRNA transcripts will be detected in intrinsic renal cells.
The specific aims define the temporal sequence of an increase in macs, interleukin 1 (IL-I) and tumor necrosis factor-(TNF) in the pathogenesis of lupus nephritis. Experiments will characterize and define the function of glomerular macs in lupus nephritis. These macs which accumulate in the mesangium are morphologically distinctive since they are laden with electron dense deposits. In addition, in culture glomerular macs are unique since they are activated, readily proliferate, and express IL-3 in addition to the cytokines characteristic of macs, IL-lB, IL-l and TNF. Using cultured and Sv40 transformed glomerular macs, studies will examine cytokine gene expression, production and regulation and determine if these macs are antigen presenters. Adoptive transfer and depletion experiments will examine the role of macs in renal injury. Finally, we will determine if IL-l attracts these macs and whether activation occurs in extra-renal sites or within the kidney. The role of IL-l and TNF in renal disease will be examined by diverse strategies that suppress and accelerate lupus nephritis, and then by measuring and correlating the level of IL-l and TNF gene expression. Conversely, IL-l and TNF and their antibodies will be administered and the progression of renal injury evaluated. Taken together these studies should clarify the importance of cytokines and macs in the progression of lupus nephritis.
| Iwata, Yasunori; Boström, Elisabeth A; Menke, Julia et al. (2012) Aberrant macrophages mediate defective kidney repair that triggers nephritis in lupus-susceptible mice. J Immunol 188:4568-80 |
| Menke, Julia; Kriegsmann, Jörg; Schimanski, Carl Christoph et al. (2012) Autocrine CSF-1 and CSF-1 receptor coexpression promotes renal cell carcinoma growth. Cancer Res 72:187-200 |
| Menke, Julia; Iwata, Yasunori; Rabacal, Whitney A et al. (2011) Distinct roles of CSF-1 isoforms in lupus nephritis. J Am Soc Nephrol 22:1821-33 |
| Menke, Julia; Bork, Tillmann; Kutska, Birte et al. (2011) Targeting transcription factor Stat4 uncovers a role for interleukin-18 in the pathogenesis of severe lupus nephritis in mice. Kidney Int 79:452-63 |
| Menke, Julia; Rabacal, Whitney A; Byrne, Katelyn T et al. (2009) Circulating CSF-1 promotes monocyte and macrophage phenotypes that enhance lupus nephritis. J Am Soc Nephrol 20:2581-92 |
| Menke, Julia; Iwata, Yasunori; Rabacal, Whitney A et al. (2009) CSF-1 signals directly to renal tubular epithelial cells to mediate repair in mice. J Clin Invest 119:2330-42 |
| Menke, Julia; Zeller, Geraldine C; Kikawada, Eriya et al. (2008) CXCL9, but not CXCL10, promotes CXCR3-dependent immune-mediated kidney disease. J Am Soc Nephrol 19:1177-89 |
| Kelley, Vicki Rubin (2007) Leukocyte-renal epithelial cell interactions regulate lupus nephritis. Semin Nephrol 27:59-68 |
| Zeller, Geraldine C; Hirahashi, Junichi; Schwarting, Andreas et al. (2006) Inducible co-stimulator null MRL-Faslpr mice: uncoupling of autoantibodies and T cell responses in lupus. J Am Soc Nephrol 17:122-30 |
| Schwarting, Andreas; Paul, Kathrin; Tschirner, Stefan et al. (2005) Interferon-beta: a therapeutic for autoimmune lupus in MRL-Faslpr mice. J Am Soc Nephrol 16:3264-72 |
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