Constitutive Phosphorylation of Interferon Receptor A-Associated Signaling Proteins in Systemic Lupus Erythematosus

Abstract

BackgroundOverexpression of type I interferon (IFN-I)-induced genes is a common feature of systemic lupus erythematosus (SLE) and its experimental models, but the participation of endogenous overproduction of IFN-I on it is not clear. To explore the possibility that abnormally increased IFN-I receptor (IFNAR) signaling could participate in IFN-I-induced gene overexpression of SLE, we examined the phosphorylation status of the IFNAR-associated signaling partners Jak1 and STAT2, and its relation with expression of its physiologic inhibitor SOCS1 and with plasma levels of IFNα and IFN-like activity.Methodology/Principal FindingsPeripheral blood mononuclear cells (PBMC) from SLE patients with or without disease activity and healthy controls cultured in the presence or in the absence of IFNβ were examined by immunoprecipitation and/or western blotting for expression of the two IFNAR chains, Jak1, Tyk2, and STAT2 and their phosphorylated forms. In SLE but not in healthy control PBMC, Jak1 and STAT2 were constitutively phosphorylated, even in the absence of disease activity (basal pJak1: controls vs. active SLE p<0.0001 and controls vs. inactive SLE p = 0.0006; basal pSTAT2: controls vs. active and inactive SLE p<0.0001). Although SOCS1 protein was slightly but significantly decreased in SLE in the absence or in the presence of IFNβ (p = 0.0096 to p<0.0001), in SOCS1 mRNA levels were markedly decreased (p = 0.036 to p<0.0001). IFNβ induced higher levels of the IFN-I-dependent MxA protein mRNA in SLE than in healthy controls, whereas the opposite was observed for SOCS1. Although there was no relation to increased serum IFNα, active SLE plasma could induce expression of IFN-dependent genes by normal PBMC.Conclusions/SignificanceThese findings suggest that in some SLE patients IFN-I dependent gene expression could be the result of a low IFNAR signaling threshold.

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

“…Three studies have previously shown higher levels of SOCS1 message in SLE patients, while one study did not find any difference in SOCS1 mRNA levels with respect to SLE. In two recent studies, SOCS1 message levels were indeed lower in SLE patients . In agreement with the latter studies, our results show that message and protein levels of SOCS1 are lower in SLE patients compared to controls.…”

“…Although the discrepancy in the SOCS1 levels among the patients in the various studies remains unclear, one possible area of distinction may lie in the different analysis methods used to measure the SOCS levels. Notably, the studies that observed higher levels of SOCS1 concluded their results based on only message levels, whereas our current study and Gabriela's study noted lower levels of SOCS1 through combined analysis of message and protein levels. A second possibility accounting for the discrepancy lies within the differential exclusionary criteria, in particular the inclusion of patients receiving prednisone treatment, as our current human studies and previous rodent studies show that corticosteroids mediate the upregulation of SOCS1 .…”

SOCS1 is a negative regulator of metabolic reprogramming during sepsis

“…We speculate that these conflicting results could be due to differences in sepsis severity and/or the time points studied. Indeed, alterations in SOCS1 expression have been associated with disease severity for several inflammatory disorders (48,(56)(57)(58). To further determine whether SOCS1 expression is increased in patients with sepsis, we employed transcriptomic analysis and found elevated levels of SOCS1 in peripheral blood cells from septic pediatric patients as compared with healthy subjects.…”

SOCS signaling in autoimmune diseases: Molecular mechanisms and therapeutic implications

“…Collectively, SOCS1 might act to avoid aberrant activation of B cells and CD4 + T cells, underscoring a critical role for SOCS1 deregulation in the development of systematic autoimmune diseases such as SLE. Indeed, patients with SLE exhibit defects in SOCS1 production, and these defects associate, at least in part, with hyper-sensitivity to type I IFNs and upregulation of JAK1 and STAT2 phosphorylation [39]. These findings suggest that in SLE pathogenesis, SOCS1 acts as a response attenuator through the negative regulation of the type I IFNs-JAK-STAT pathway signaling [40].…”