Objective: MRL-Fas(lpr) mice spontaneously develop an autoimmune disease that mimics systemic lupus erythematosus in humans. Infiltrating T cells expressing interferon-gamma (IFNgamma) are responsible for the autoimmune kidney destruction in MRL-Fas(lpr) mice, and interleukin-18 (IL-18) released by mononuclear phagocytes stimulates T cells to produce the IFNgamma. Since MRL-Fas(lpr) T cells are characterized by an overexpression of the IL-18 receptor accessory chain, we sought to determine the impact of IL-18 on the progression of lupus nephritis in MRL-Fas(lpr) mice.
Methods: IL-18 expression in sera and kidney tissues from MRL-Fas(lpr) mice was determined by enzyme-linked immunosorbent assay (ELISA), reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, and Western blotting. IL-18 production by primary cultured tubular epithelial cells (TECs) from MRL-Fas(lpr) and BALB/c mice were examined by RT-PCR, ELISA, and Western blotting. The interactions of TEC-derived IL-18 and MRL-Fas(lpr) T cells were studied in coculture assays. IL-18-related effects on TEC viability and adhesion molecule expression were determined by fluorescence-activated cell sorting and cell proliferation assays.
Results: Up-regulation of mature IL-18 was restricted to nephritic MRL-Fas(lpr) kidneys and increased in parallel with the severity of lupus nephritis. IL-18 expression was not confined to infiltrating monocytes but was primarily detected in TECs. Similarly, interleukin-1beta-converting enzyme expression, which is required for the processing of precursor IL-18, was localized in TECs. De novo synthesis of IL-18 by MRL-Fas(lpr) TECs was confirmed by RT-PCR and Western blotting. Functional assays revealed that activated TECs induced IFNgamma production in MRL-Fas(lpr) T cells through IL-18. IL-18, in turn, increased apoptotic TEC death and up-regulation of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1.
Conclusion: Taken together, our findings suggest that IL-18-producing TECs may directly be involved in the pathogenesis of lupus nephritis.