Stat4 Isoforms Differentially Regulate Inflammation and Demyelination in Experimental Allergic Encephalomyelitis

摘要

Experimental allergic encephalomyelitis (EAE) is a T cell-mediated autoimmune disease model of multiple sclerosis (MS). Signal transducer and activator of transcription 4 (Stat4) is a transcription factor activated by interleukin 12 (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 shown earlier 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 Stat4α. In this study we examined whether T cells expressing either isoform could impact the pathogenesis of EAE. We found that transgenic mice expressing Stat4βon a Stat4-deficient background develop an exacerbated EAE compared to wild-type mice following immunization with MOGp35–55 peptide, while Stat4α transgenic mice have greatly attenuated disease. The differential development of EAE in transgenic mice correlates with increased IFNγ and IL-17 in Stat4β-expressing cells in situ, contrasting increased IL-10 production by Stat4α-expressing cells. This study demonstrates that Stat4 isoforms differentially regulate inflammatory cytokines in association with distinct effects on the onset and severity of EAE.