Therapeutic Potential for Targeting the Suppressor of Cytokine Signalling‐1 Pathway for the Treatment of SLE

Abstract

Although the specific events dictating systemic lupus erythematosus (SLE) pathology remain unclear, abundant evidence indicates a critical role for dysregulated cytokine signaling in disease progression. Notably, the suppressor of cytokine signaling (SOCS) family of intracellular proteins, in particular the kinase inhibitory region (KIR) bearing SOCS1 and SOCS3, play a critical role in regulating cytokine signaling. To assess a relationship between SOCS1/SOCS3 expression and SLE, the goals of this study were to: 1) evaluate the time kinetics of SOCS1/SOCS3 message and protein expression based on SLE associated stimulations, 2) compare levels of SOCS1 and SOCS3 present in SLE patients and healthy controls by message and protein, 3) relate SOCS1/SOCS3 expression to inflammatory markers in SLE patients, and 4) correlate SOCS1/SOCS3 levels to current treatments. We found that SOCS1 and SOCS3 were most abundant in murine splenic samples at 48 hours subsequent to stimulation by anti-CD3, LPS, or interferon gamma. In addition, significant reductions in SOCS1 and SOCS3 were present within PMBC’s of SLE patients compared to controls by both mRNA and protein expression. We also found that decreased levels of SOCS1 in SLE patients were correlated to enhanced levels of inflammatory markers and up-regulated expression of MHC class II. Finally, we show that patients receiving steroid treatment possessed higher levels SOCS1 compared to SLE patient counterparts, and that steroid administration to human PBMCs up-regulated SOCS1 message in a dose and time dependent manner. Together, these results suggest that therapeutic strategies focused on SOCS1 signaling may have efficacy in the treatment of SLE.

Defective Suppressor of Cytokine Signaling 1 Signaling Contributes to the Pathogenesis of Systemic Lupus Erythematosus

“…Excessive production of IFN-γ and aberrant control of the IFN-γ signaling pathway have been implicated in the pathogenesis of SLE in BWF1 mice ( 25 ). In lupus-prone (NZB × NZW) F1 mice, SOCS1 expression was decreased, whereas pSTAT1 was increased in spleen-derived lymphocytes, thus mirroring the results of SOCS1 expression in peripheral blood mononuclear cells of patients with SLE ( 12 ). hCDR1 is a tolerogenic peptide derived from the sequence of the first complementarity-determining region (CDR1) of anti-DNA immunoglobulin (Ig) G, and it can downregulate pathogenic cytokines, such as tumor necrosis factor (TNF)-α, IL-1β, and IFN-γ, and upregulate the immunosuppressive cytokine TGF-β in lupus-prone mice ( 25 ).…”

“…In these murine models, SOCS1 was upregulated upon subcutaneous administration of hCDR1, accompanied by pSTAT1 downregulation and tempered IFN-γ signaling ( 25 ). Moreover, patients undergoing prednisone treatment exhibited higher SOCS1 protein levels than those not receiving prednisone ( 12 ). Therefore, these findings suggest that SOCS1 insufficiency results in unbridled downstream signaling and contributes to the development and progression of SLE, whereas upregulation of SOCS1 definitely alleviates the course of SLE.…”

“…Recent studies have demonstrated that SOCS1 participates in the pathogenesis of SLE ( 11 , 12 ). The mRNA expression level of SOCS1 is significantly decreased in peripheral blood mononuclear cells of patients with SLE ( 11 ).…”

“…SOCS1 is also involved in other pathological processes of SLE including activation of immune cells, production of proinflammatory factors, initiation of renal fibrosis, etc. ( 12 ). The upregulation of SOCS1 through alternative methods is beneficial to improve the conditions of SLE patients ( 12 , 13 ).…”

“…( 12 ). The upregulation of SOCS1 through alternative methods is beneficial to improve the conditions of SLE patients ( 12 , 13 ). In this review, we summarized recent studies on the function of SOCS1 in the pathogenesis of SLE and elaborated its clinical significance and therapeutic implications.…”