SLE progression in human and murine SLE is accompanied by cell and pathway specific negative regulation of cytokine signal transduction

Abstract

Systemic lupus erythematosus (SLE) is a cyclic, persistent disease of unknown etiology, with multiple lines of evidence supporting a model in which aberrant regulation of cytokine signaling pathways promote and sustain SLE. Postulating that such mechanisms may be disturbed in SLE patients, we used phospho‐specific flow cytometry to perform an extensive profile of cytokine signaling in a murine model of SLE and 47 human patients, revealing disease course‐dependent, cell type, and pathway specific negative regulation of the JAK‐STAT signal transduction pathways induced by the interferons. Specific down‐regulation of Stat1, Stat3, Stat5 responses in different immune cell subtypes was correlated with upregulated SOCS1 protein expression. SLE pathology involving the prominent IFNα model is here expanded to include additional signaling nodes, coupling these systems to negative feedback regulation. Pathogenic coupling of positive and negative feedback regulation may explain the cyclic nature of human SLE.This work was supported by NHLBI Proteomics Center contract N01‐HV‐28183 and NIH grant 8‐PA1036535C