Dysregulation of the suppressor of cytokine signalling 3–signal transducer and activator of transcription‐3 pathway in the aetiopathogenesis of S jögren's syndrome

Summary The suppressor of cytokine signalling 3 ( SOCS 3) negatively regulates the J anus kinase ( JAK )/signal transducer and activator of transcription‐3 ( STAT ‐3)/interleukin ( IL )‐17 pathway. The proinflammatory cytokine IL ‐17 is over‐expressed in S jögren'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 SOCS 3. The expression of SOCS 3 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 SOCS 3 and IL ‐17. IL ‐6‐stimulated PBMC from SS and controls were evaluated for time‐dependent STAT ‐3 activation and SOCS 3 induction, and for IL ‐17 expression. Immunoblotting revealed greater levels of SOCS 3 in PBMC from SS than SC ( P  = 0·017) or HC ( P  < 0·001). Similarly, the proportion of salivary‐gland tissue cells staining for SOCS 3 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 SOCS 3 or IL ‐17. However, there was a high frequency of SOCS 3/ 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 SOCS 3, and enhanced expression of IL ‐17. This study showed that SOCS 3 expression is up‐regulated in SS . However, the absence in SS of the normal inverse relationship between SOCS 3 and p STAT ‐3/ IL ‐17 indicates a functional disturbance in this signalling cascade. Consequently, a reduction in function, rather than a reduction in expression of SOCS 3 accounts for the unregulated expression of IL ‐17 in SS , and may play a crucial role in aetiopathogenesis.