The lymphoproliferativelprgene confers a lupus-like disease with lymphadenopathy, antinuclear antibody production, and glomerulonephritis in MRL-lpr/lprmice. Upregulation of ornithine decarboxylase (ODC) activity and polyamine levels have been observed in the kidney and lymphoid organs of this strain. Inhibition of ODC with 0.5–1.5% (w/v) difluoromethylornithine (DFMO) in drinking water prolonged life-span and ameliorated renal disease. Glomerulonephritis is a major cause of morbidity and mortality in human and murine lupus. In order to elucidate the mechanism(s) of ODC regulation in lupus nephritis, we characterized ODC at the protein and mRNA levels in 3 strains of autoimmune mice with thelprgenetic background (MRL-lpr/lpr, C3H-lpr/lprand C57BL/6J-lpr/lpr) using Western blotting, enzyme kinetics, turnover rate measurements, Northern blot hybridization, and reverse transcription-polymerase chain reaction (RT-PCR). Normal BALB/c mice were used as a control. We found that ODC activity in the kidney oflprstrains was 4-to 6-fold higher than that of BALB/c mice. The intensity of the major ODC protein band at 54 kD in Western blot was 4-fold higher in MRL-lpr/lprand C3H-lpr/lprkidney compared to that of BALB/c kidney. Putrescine levels were 2-to 4-fold higher in kidney oflprstrains than that of BALB/c and DFMO-treated MRL-lpr/lprmice. DFMO treatment significantly reduced ODC activity and polyamine levels. The half-life of ODC enzyme in MRL-lpr/lpr, C3H-lpr/lpr, B6-lpr/lprand BALB/c mouse kidneys was 15, 5, 8 and 23 min, respectively. There was no significant difference in the Kmvalues of different strains, whereas Vmaxvalues differed significantly. There was no difference in the level of SAMDC, another enzyme involved in the polyamine biosynthetic pathway, in various strain. Steady-state levels of ODC mRNA were lower inlprstrains compared to that of BALB/c mouse. Our results suggest that the basis for up-regulation of ODC is not at the transcriptional level, but may involve post-transcriptional modification(s) inlprstrains. The link between aberrant regulation of ODC and the immunopathogenesis of murine lupus nephritis indicates novel targets for lupus therapy.