Targeting of the transcription factor STAT4 by antisense phosphorothioate oligonucleotides suppresses collagen-induced arthritis.
The transcription factor STAT4 mediates signals of various proinflammatory cytokines, such as IL-12, IL-15, and IL-23, that initiate and stabilize Th1 cytokine production. Although Th1 cytokine production has been suggested to play a major pathogenic role in rheumatoid arthritis, the role of STAT4 in this disease is poorly understood. In this study, we demonstrate a key functional role of STAT4 in murine collagen-induced arthritis (CIA). In initial studies we found that STAT4 expression is strongly induced in CD4(+) T cells and to a lesser extent in CD11b(+) APCs during CIA. To analyze the role of STAT4 for arthritis manifestation, we next investigated the outcome of interfering with STAT4 gene expression in CIA by using STAT4-deficient mice. Interestingly, STAT4-deficient mice developed significantly less severe arthritis than wild-type control mice and the T cells from such mice produced less IL-6, TNF, and IL-17. In addition, the targeting of STAT4 expression by a specific antisense phosphorothioate oligonucleotide directed at the translation start site suppressed STAT4 levels and signs of CIA even when applied during the onset of disease manifestation. These data suggest a key regulatory role of STAT4 in the pathogenesis and manifestation of murine collagen-induced arthritis. Furthermore, the targeting of STAT4 emerges as a novel approach to therapy for chronic arthritis.
Hildner
Kai M
KM
Laboratory of Immunology, I Medical Clinic, University of Mainz, Langenbeckstrasse 1, Mainz, Germany. Kai.Hildner@gmx.net
Schirmacher
Peter
P
Atreya
Imke
I
Dittmayer
Maria
M
Bartsch
Brigitte
B
Galle
Peter R
PR
Wirtz
Stefan
S
Neurath
Markus F
MF
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000473:pathology; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D039481:CD11b Antigen / Q000276:immunology; D002478:Cells, Cultured; D018387:Codon, Initiator / Q000037:antagonists & inhibitors / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D050797:STAT4 Transcription Factor / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology; D013873:Thionucleotides / Q000494:pharmacology*
D039481:CD11b Antigen; D018387:Codon, Initiator; D016376:Oligonucleotides, Antisense; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D013873:Thionucleotides