Dysregulation of the suppressor of cytokine signalling 3–signal transducer and activator of transcription-3 pathway in the aetiopathogenesis of Sjögren's syndrome

Abstract

SummaryThe suppressor of cytokine signalling 3 (SOCS3) negatively regulates the Janus kinase (JAK)/signal transducer and activator of transcription-3 (STAT-3)/interleukin (IL)-17 pathway. The proinflammatory cytokine IL-17 is overexpressed in Sjögren's syndrome (SS) and is a key factor in its pathogenesis. We hypothesized that IL-17 over-expression in SS results from ineffective regulation by SOCS3. The expression of SOCS3 was analysed in peripheral blood mononuclear cells (PBMC) from SS cases, sicca controls (SC) and healthy controls (HC) and tissue samples from SS, SC and healthy salivary glands (HSG). PBMC and salivary gland tissue from SS and controls were dual-immunostained for SOCS3 and IL-17. IL-6-stimulated PBMC from SS and controls were evaluated for time-dependent STAT-3 activation and SOCS3 induction, and for IL-17 expression. Immunoblotting revealed greater levels of SOCS3 in PBMC from SS than SC (P = 0·017) or HC (P < 0·001). Similarly, the proportion of salivary-gland tissue cells staining for SOCS3 was significantly higher in SS than SC (P = 0·029) or HSG (P = 0·021). The cells in PBMC/salivary gland samples from controls predominantly expressed either SOCS3 or IL-17. However, there was a high frequency of SOCS3/IL-17 co-expression within cells of SS samples. IL-6-stimulation of PBMC from SS cases revealed prolonged activation of STAT-3 with reduced negative regulation by SOCS3, and enhanced expression of IL-17. This study showed that SOCS3 expression is up-regulated in SS. However, the absence in SS of the normal inverse relationship between SOCS3 and pSTAT-3/IL-17 indicates a functional disturbance in this signalling cascade. Consequently, a reduction in function, rather than a reduction in expression of SOCS3 accounts for the unregulated expression of IL-17 in SS, and may play a crucial role in aetiopathogenesis.

Cytokine-induced STAT1 activation is increased in patients with primary Sjögren's syndrome

“…Our data would imply that this is probably not the case, since the expression of both SOCS1 and SOCS3 mRNA was found to be increased in pSS patients compared with healthy controls. Increased local or systemic expression of SOCS1 and SOCS3 in patients with pSS was also demonstrated in two recent studies [31,32]. We hypothesize that up-regulated SOCS1 expression in circulating PBMCs from pSS patients may prevent constitutive STAT1 phosphorylation in these cells that are normally exposed to rather low levels of STAT1-activating cytokines.…”

Sjogren’s Syndrome and TAM Receptors: A Possible Contribution to Disease Onset

“…As discussed, TAM receptors are well-characterized molecules that contribute to both efferocytosis and dampening of the IFN response as illustrated in Figure 2. SOCS3 is an essential negative regulatory component in the proinflammatory process; however, its level and/or activity appeared to be significantly reduced in SS [111, 121]. While the status of SOCS3 expression in SS requires further clarification, lack of SOCS3 expression or SOCS3 activity represents an appealing mechanism to account for the failure to rein in inflammatory signaling in SS.…”

“…These conflicting results concerning TAM ligand expression in SS are also reflected in SLE where one study reported higher levels of Gas6 and lower Pros1 in the plasma of SLE patients [118], while other groups have detected decreased Gas6 in the plasma of SLE patients [119], or little difference in plasma Gas6 and Pros1 between controls and SLE patients [120]. It has been observed that while SOCS3 is upregulated in PBMCs and labial salivary gland of pSS patients, negative regulation of cytokine signaling fails to occur [121], suggesting that SOCS3-mediated reductions in inflammatory signaling are defective in SS. Together, these results suggest that the crucial TAM activities of suppressing IFN signaling and efferocytosis may be impaired in SS.…”

Regulation of IL-17 in autoimmune diseases by transcriptional factors and microRNAs

“…In addition, IL-25 and IL-27 have been found to negatively regulate Th17 cells ( Batten et al, 2006 ; Kleinschek et al, 2007 ; Tang et al, 2015 ). Suppressor of cytokine signaling (SOCS3) also negatively regulates IL-6-gp160 signal transduction resulting in decreased IL-17 ( Babon et al, 2014 ; Vartoukian et al, 2014 ). FoxP3 interacts directly with RORγt through the exon 2 region and forkhead domain of FoxP3 and suppresses the activation of the IL-17 promoter ( Ichiyama et al, 2008 ).…”