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

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