Targeting transcription factor Stat4 uncovers a role for interleukin-18 in the pathogenesis of severe lupus nephritis in mice.

Abstract

Polymorphisms in the transcription factor Stat4 gene have been implicated as risk factors for systemic lupus erythematosus. Although some polymorphisms have a strong association with autoantibodies and nephritis, their impact on pathophysiology is still unknown. To explore this further we used signal transducers and activators of transcription 4 (Stat4) knockout MRL/MpJ-Fas(lpr)/Fas(lpr) (MRL-Fas(lpr)) mice and found that they did not differ in survival or renal function from Stat4-intact MRL-Fas(lpr) mice. Circulating interleukin (IL)-18 levels, however, were elevated in Stat4-deficient compared to Stat4-intact mice, suggesting that this interleukin might contribute to the progression of lupus nephritis independent of Stat4. In a second approach, Stat4 antisense or missense oligonucleotides or vehicle were given to MRL-Fas(lpr) mice with advanced nephritis. Each of these treatments temporarily ameliorated disease, although IL-18 was increased in each setting. Based on these findings, studies using gene transfer to overexpress IL-18 in MRL-Fas(lpr) and IL-12p40/IL-23 knockout MRL-Fas(lpr) mice reveal a critical role for IL-18 in mediating disease. Thus, the Stat4 and IL-12 (an activator of Stat4)-independent factor, IL-18, can drive autoimmune lupus nephritis in MRL-Fas(lpr) mice. Temporarily blocking Stat4 during advanced nephritis ameliorates disease, suggesting a time-dependent compensatory proinflammatory mechanism.

• Authors: Julia Menke, Tillmann Bork, Birte Kutska, Katelyn T Byrne, Michaela Blanfeld, Manfred Relle, Vicki R Kelley, Andreas Schwarting
• Journal: Kidney international (Kidney Int) Vol. 79 Issue 4 Pg. 452-63 (Feb 2011) ISSN: 1523-1755 [Electronic] United States
• PMID: 20980973 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA Primers
• Interleukin-18
• Interleukin-23
• Oligodeoxyribonucleotides, Antisense
• STAT4 Transcription Factor
• Stat4 protein, mouse
• Interleukin-12
• Interferon-gamma

Topics

• Animals
• Base Sequence
• DNA Primers (genetics)
• Female
• Gene Knockout Techniques
• Gene Transfer Techniques
• Interferon-gamma (biosynthesis)
• Interleukin-12 (metabolism)
• Interleukin-18 (antagonists & inhibitors, genetics, metabolism)
• Interleukin-23 (metabolism)
• Kidney (metabolism, pathology)
• Lupus Nephritis (etiology, genetics, metabolism, pathology)
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred MRL lpr
• Mice, Knockout
• Oligodeoxyribonucleotides, Antisense (genetics, pharmacology)
• STAT4 Transcription Factor (antagonists & inhibitors, deficiency, genetics)