Interferon-γ signaling inhibition by a suppressor of cytokine signaling-1 (SOCS-1) mimetic peptide ameliorates lupus pathology in a spontaneous mouse model.

Abstract

Abstract Cytokine-mediated dysregulation of the Jak/STAT pathway is closely associated with systemic lupus erythematosus (SLE) onset and progression. In the MRLlpr/lprmouse model of spontaneous SLE, aberrant IFN-γ signaling is critical for onset and progression. Notably, Suppressor of Cytokine Signaling-1 (SOCS-1) is known to regulate proinflammatory cytokine production. We have previously shown that a peptide mimicking SOCS1 signaling (SOCS1-KIR) inhibited IFN-γ signaling and auto-inflammatory disease progression. SOCS1-KIR mimics the ability of native SOCS1 to inactivate signal cascade propagation by Jak2 and Tyk2. In this study we test the hypothesis that SOCS1-KIR administration will inhibit lupus pathology in MRLlpr/lpr mice. A 3x/week administration of SOCS1-KIR mediated a statistically significant reduction in lupus associated lymphadenopathy. Mechanistically, SOCS1-KIR inhibited the generation of IFN-γ+ CD8+ and IFN-γ+ CD4+ memory T lymphocytes in vivo and in vitro. Additionally, the mechanistic specificity of SOCS1-KIR was delineated through in vitro culturing experiments with a Jak/STAT agonist, which restored the generation of IFN-γ+ memory T lymphocytes. These data show that administration of a SOCS1-KIR peptide has the ability to limit lupus-associated pathology, in part through regulation of IFN-γ signaling. In addition, these data suggest that strategies targeting regulation of excessive Jak/STAT signaling such as, the use of SOCS1-KIR, should be considered as a therapeutic, due to its ability to dampen excessive cytokine help often observed in disease onset and progression.