title: 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.affiliation: Department of Internal Medicine, Division of Rheumatology and Clinical Immunology, Johannes Gutenberg University, Mainz, Germany. julia.menke@unimedizin-mainz.de
authors.forename: Julia
authors.initials: J
authors.lastname: Menke
authors.forename: Tillmann
authors.initials: T
authors.lastname: Bork
authors.forename: Birte
authors.initials: B
authors.lastname: Kutska
authors.forename: Katelyn T
authors.initials: KT
authors.lastname: Byrne
authors.forename: Michaela
authors.initials: M
authors.lastname: Blanfeld
authors.forename: Manfred
authors.initials: M
authors.lastname: Relle
authors.forename: Vicki R
authors.initials: VR
authors.lastname: Kelley
authors.forename: Andreas
authors.initials: A
authors.lastname: Schwarting
mesh_terms: 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
chemical_list: 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