Targeting of the transcription factor STAT4 by antisense phosphorothioate oligonucleotides suppresses
Kai M Hildner1, Peter Schirmacher, Imke Atreya
1Laboratory of Immunology, I Medical Clinic, University of Mainz, Langenbeckstrasse 1, Mainz, Germany. Kai.Hildner@gmx.net
Abstract:
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.
Insights
Signal transducer and activator of transcription 4 (STAT4) plays a key role in rheumatoid arthritis pathogenesis. Inhibiting STAT4 reduces arthritis severity, suggesting it as a potential therapeutic target for chronic arthritis.
Area of Science:
- Immunology
- Molecular Biology
- Rheumatology
Background:
- Rheumatoid arthritis (RA) pathogenesis involves Th1 cytokines.
- The role of Signal transducer and activator of transcription 4 (STAT4) in RA is not well understood.
- STAT4 mediates signals for key proinflammatory cytokines like IL-12, IL-15, and IL-23.
Purpose of the Study:
- To investigate the functional role of STAT4 in murine collagen-induced arthritis (CIA).
- To assess the therapeutic potential of targeting STAT4 in arthritis.
Main Methods:
- Utilized STAT4-deficient mice to study arthritis development.
- Analyzed STAT4 expression in CD4(+) T cells and CD11b(+) APCs during CIA.
- Administered an antisense phosphorothioate oligonucleotide targeting STAT4.
Main Results:
- STAT4-deficient mice exhibited significantly reduced arthritis severity compared to wild-type controls.
- T cells from STAT4-deficient mice produced lower levels of IL-6, TNF, and IL-17.
- STAT4 targeting suppressed disease signs, even when initiated during disease onset.
Conclusions:
- STAT4 is a key regulator in the pathogenesis and manifestation of murine CIA.
- Targeting STAT4 represents a novel therapeutic strategy for chronic arthritis.
