MRL‐Fas^lpr mice spontaneously develop an autoimmune disease that mimics systemic lupus erythematosus in humans. Infiltrating T cells expressing interferon‐γ (IFNγ) 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 IFNγ. 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.

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.

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‐1β–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 IFNγ 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.

Taken together, our findings suggest that IL‐18–producing TECs may directly be involved in the pathogenesis of lupus nephritis.