Targeting transcription factor Stat4 uncovers a role for interleukin-18 in the pathogenesis of severe lupus nephritis in mice.
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.
Menke
Julia
J
Department of Internal Medicine, Division of Rheumatology and Clinical Immunology, Johannes Gutenberg University, Mainz, Germany. julia.menke@unimedizin-mainz.de
Bork
Tillmann
T
Kutska
Birte
B
Byrne
Katelyn T
KT
Blanfeld
Michaela
M
Relle
Manfred
M
Kelley
Vicki R
VR
Schwarting
Andreas
A
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D005260:Female; D055786:Gene Knockout Techniques; D018014:Gene Transfer Techniques; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000378:metabolism; D020382:Interleukin-18 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D053759:Interleukin-23 / Q000378:metabolism; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008181:Lupus Nephritis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D050797:STAT4 Transcription Factor / Q000037:antagonists & inhibitors / Q000172:deficiency* / Q000235:genetics
D017931:DNA Primers; D020382:Interleukin-18; D053759:Interleukin-23; D020319:Oligodeoxyribonucleotides, Antisense; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D018664:Interleukin-12; D007371:Interferon-gamma