Distinct roles of STAT4α and STAT4β in the pathogenesis of experimental allergic encephalomyelitis (B99)

Abstract

Abstract Experimental allergic encephalomyelitis (EAE) is a T cell-mediated autoimmune disease model of multiple sclerosis (MS). Interleukin 12 (IL-12) and IL-23 are heterodimeric cytokines, which share common IL-12p40/IL-12Rb2 subunits and play distinct roles in the pathogenesis of EAE. Signaling through JAK-STAT pathway, IL-12 induces Th1 cell development, while IL-23 enhances ThIL17 cell differentiation. We and other have shown earlier that therapeutic intervention or targeted disruption of STAT4 was effective in ameliorating EAE. Recent studies have identified the expression of a full-length STAT4α and a truncated STAT4β, which lacks 44 amino acids at the C-terminus. In this study we show that the STAT4β transgenic mice, induced to develop EAE by immunization with MOGp35-55 peptide, develop an exacerbated EAE than the wild type littermates. However, the STAT4α transgenic mice remain resistant to EAE, as seen in STAT4 knockout mice. Further analyses, by real-time PCR, ELISA and Western blot, show that STAT4β transgenic mice express higher levels of IFNγ, IL-17, IL-12, IL-23 and IL-27 in the brain and spleen than STAT4α transgenic mice, which correlates with the clinical outcome of EAE. Although the distinct roles played by STAT4α and STAT4β in IL-12 and IL-23 signaling in EAE is not known, this study validates the use of STAT4β as a novel therapeutic target in the treatment of MS and other autoimmune diseases.