A novel role of SOCS-4 and SOCS-5 in cytokine signalling

Abstract

The immune system is propagated by cytokines and their intracellular signal transduction. To ensure an appropriate immune response, these signalling pathways are tightly controlled. One such regulatory mechanism is the induction of a family of 8 intracellular proteins called Suppressor of Cytokine Signalling (CIS [Cytokine-inducible SH2 protein] and SOCS1-7). Many cytokines and pathogenic stimuli have been shown to regulate SOCS expression, which subsequently act by binding to components of the intracellular pathway and thus block the cascade of signalling events. CIS, SOCS1-3 are the most comprehensively described SOCS proteins, with SOCS4-7 being less well understood. Therefore, this project aimed to investigate the role of 2 of these 'neglected SOCS', SOCS4 and SOCS5 and their involvement in the signal transduction of pro-inflammatory (TNF-α, IL-6 and IL-1β) and anti-viral (IFN-) cytokines. Indeed, we discovered that both SOCS4 and SOCS5 mRNA and expression were induced by these cytokines, to varying degrees. Interestingly, while SOCS4 overexpression inhibited IL-6-mediated STAT3 phosphorylation, SOCS5 expression enhanced IL-6-mediated pSTAT3 levels. However, SOCS5 expression acted to reduce TNF-α-mediated IκBα degradation. Together these findings reveal for the first time, that both SOCS4 and SOCS5 are induced by pro-inflammatory and anti-viral cytokines and that SOCS5 can regulate pro-inflammatory signalling of both IL-6 and TNF-, and while SOCS4 has no inhibitory effect upon TNF- signaling, it acts to reduce pro-inflammatory responses of IL-6. These discoveries have not only revealed that SOCS4 and SOCS5 expression are regulated, but have shed light upon new immune regulatory mechanisms for both of these proteins.