The therapeutic effects of a suppressor of cytokine signaling 1 mimetic peptide in experimental allergic encephalomyelitis, a murine model of multiple sclerosis.

摘要

Suppressors of cytokine signaling (SOCS) negatively regulate several facets of the immune system by interfering with the Janus kinas/signal transducers and activators of transcription (JAK/STAT) pathway employed by many cytokines. By blocking phosphorylation of the Janus kinase activation loop, the cytokine receptor, and/or the associated STAT, SOCS proteins inhibit downstream intracellular signaling. SOCS also target bound proteins for proteasomal degradation via the SOCS Box, which serves as an E3-ubiquitin ligase. We have developed a small peptide corresponding to the amino acid sequence of the kinase inhibitory region (KIR) of SOCS-1, SOCS1-KIR. This peptide was found to mimic the effects of SOCS-1 in vitro.;Using the murine model of relapsing/remitting multiple sclerosis (MS), experimental allergic encephalomyelitis (EAE), we have evaluated the therapeutic effects of SOCS1-KIR in vivo. SJL/J mice were given a regimen of SOCS1-KIR or control treatments beginning 12 days post-immunization with myelin basic protein (MBP). While 100% of control mice experienced some form of observable symptoms, 20% of SOCS1-KIR treated mice never became visibly ill. Treated mice that did become sick had significantly lower maximum average disease severity than control mice, and fewer treated mice experienced fatal disease compared to the controls. Additionally, lymphocyte infiltration into the central nervous system (CNS) is reversed and blocked by treatment with SOCS1-KIR.;Interleukin-17 producing T-cells (Th17 cells) have recently been identified as the key effector cells in MS and its murine counterpart EAE. Splenocytes from treated mice were found to produce less IL-17A, both before and after re-stimulation with MBP, and SOCS1-KIR was found to inhibit production of IL-17A by MBP-sensitive splenocytes. Additionally, SOCS1-KIR inhibited MBP-stimulated cell proliferation. SOCS1-KIR was also determined to inhibit production of IL-17A and interferon gamma (IFNgamma) after stimulation of MBP-sensitized splenocytes with IL-23, a key mediator of Th17 cell function. SOCS1-KIR was shown to inhibit IL-23-induced STAT3 phosphorylation. These results indicate that SOCS1-KIR inhibits cytokine production by Th17 cells and prevents the development of severe relapsing paralysis in mice. Thus, we have developed a peptide that functions as a SOCS-1 mimetic and which has potential therapeutic value with regards to autoimmune diseases like MS.