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Targeting of the Transcription Factor STAT4 by Antisense Phosphorothioate Oligonucleotides Suppresses Collagen-Induced Arthritis¹

Kai M. Hildner^2,*, Peter Schirmacher, Imke Atreya^*, Maria Dittmayer^*, Brigitte Bartsch^*, Peter R. Galle^*, Stefan Wirtz^* and Markus F. Neurath^2,*

^* Laboratory of Immunology, I Medical Clinic, University of Mainz, Mainz, Germany; and Institute of Pathology, University of Heidelberg, Heidelberg, Germany

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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ The research of K.M.H. and M.F.N. was supported by the Mainz-Forschungsfonds (MAIFOR) program of the University of Mainz and the Sonderforschungsbereich Grant SFB548 of the Deutsche Forschungsgemeinschaft.

² Address correspondence and reprint requests to Dr. Kai M. Hildner, Laboratory of Immunology I, Medical Clinic, University of Mainz, Langenbeckstrasse 1, Mainz, Germany; E-mail address: Kai.Hildner{at}gmx.net or Dr. Markus F. Neurath, Laboratory of Immunology I, Medical Clinic, University of Mainz, Langenbeckstrasse 1, Mainz, Germany; E-mail address: neurath{at}1-med.klinik.uni-mainz.de

³ Abbreviations used in this paper: RA, rheumatoid arthritis; AS, antisense; CIA, collagen-induced arthritis; CII, chicken collagen type II; EAE, experimental autoimmune encephalomyelitis; i.d., intradermally; MM, mismatched; WT, wild type.

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