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* Neuroscience Research Laboratory, Methodist Research Institute, Indianapolis, IN 46202;
Department of Medicine and
Departments of Pediatrics, Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202; and
School of Informatics, Indiana University–Purdue University at Indianapolis, Indianapolis, IN 46202
Experimental allergic encephalomyelitis (EAE) is a T cell-mediated autoimmune disease model of multiple sclerosis. Signal transducer and activator of transcription 4 (Stat4) is a transcription factor activated by IL-12 and IL-23, two cytokines known to play important roles in the pathogenesis of EAE by inducing T cells to secrete IFN-
and IL-17, respectively. We and others have previously shown that therapeutic intervention or targeted disruption of Stat4 was effective in ameliorating EAE. Recently, a splice variant of Stat4 termed Stat4β has been characterized that lacks 44 amino acids at the C terminus of the full-length Stat4
. In this study we examined whether T cells expressing either isoform could affect the pathogenesis of EAE. We found that transgenic mice expressing Stat4β on a Stat4-deficient background develop an exacerbated EAE compared with wild-type mice following immunization with myelin oligodendrocyte glycoprotein peptide 35–55, while Stat4 transgenic mice have greatly attenuated disease. The differential development of EAE in transgenic mice correlates with increased IFN- and IL-17 in Stat4β-expressing cells in situ, contrasting increased IL-10 production by Stat4-expressing cells. This study demonstrates that Stat4 isoforms differentially regulate inflammatory cytokines in association with distinct effects on the onset and severity of EAE.
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 This work was supported in part by National Institutes of Health Grants R01 NS42257 (to J.J.B.) and AI045515 (to M.H.K.).
2 C.M., W.C., and J.T.O. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. John J. Bright, Methodist Research Institute at Clarian Health, 1800 N. Capitol Avenue, Noyes Building Suite E-504C, Indianapolis, IN 46202. E-mail address: jbright1{at}clarian.org
4 Abbreviations used in this paper: MS, multiple sclerosis; EAE, experimental allergic encephalomyelitis; MBP, myelin basic protein; PLP, proteolipid protein; MOG, myelin oligodendrocyte glycoprotein; Stat, signal transducer and activator of transcription; qRT-PCR, quantitative RT-PCR; MCS, mean clinical score; MMCS, mean maximum clinical score; AMCS, average mean clinical score; AUC, area under the curve.
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