Intragenic regulation of SOCS3 isoforms.

BACKGROUND: Inflammatory reactions are commonly affected by stress responses. Interleukin-6 signalling is part of the inflammatory response and is stringently regulated by the feedback inhibitor SOCS3 expressed in a short and long isoform. Here, we studied the inhibitory potential of the two SOCS3 isoforms. Furthermore, we analysed the regulation of SOCS3 isoform expression and the role of PKR stress kinase signalling in SOCS3 protein expression. METHODS: We performed Western blotting, reporter assays, genetic analyses and manipulations for studying SOCS3 isoform expression and activation of signalling components involved in interleukin-6-induced and PKR-dependent signalling. RESULTS: Interleukin-6-induced endogenous expression of both SOCS3 isoforms was found in distinct cell types. Forced expression of either the long or short SOCS3 isoform demonstrated equal inhibitory activity of each isoform and confirmed longer half-life of the short isoform. Study of intragenic regulation of SOCS3 isoform expression revealed that (i) the 5'-UTR of SOCS3 mRNA restrains specifically expression of the long SOCS3 isoform, (ii) expression of the long isoform restrains expression of the short isoform, and (iii) signalling through the stress kinase PKR does not impact on SOCS3 isoform ratio. CONCLUSIONS: Both SOCS3 isoforms show a similar potential for inhibiting interleukin-6 signalling but differ in their half-lives. Relative expression of the isoforms depends on intragenic elements yet is independent of PKR signalling.

Interleukin-6 influences stress-signalling by reducing the expression of the mTOR-inhibitor REDD1 in a STAT3-dependent manner.

Interleukin 6 (IL-6) is a pleiotropic cytokine and a strong activator of Mammalian Target of Rapamycin (mTOR). In contrast, mTOR activity is negatively regulated by Regulated in Development and DNA Damage Responses 1 (REDD1). Expression of REDD1 is induced by cellular stressors such as glucocorticoids and DNA damaging agents. We show that the expression of basal as well as stress-induced REDD1 is reduced by IL-6. The reduction of REDD1 expression by IL-6 is independent of proteasomal or caspase-mediated degradation of REDD1 protein. Instead, induction of REDD1 mRNA is reduced by IL-6. The regulation of REDD1 expression by IL-6 is independent of Phosphatidylinositide-3-Kinase (PI3K) and Mitogen-Activated Protein Kinase (MAPK) signalling but depends on the expression and activation of Signal Transducer and Activator of Transcription 3 (STAT3). Furthermore, the reduction of basal REDD1 expression by IL-6 correlates with IL-6-induced activation of mTOR signalling. Inhibition of STAT3 activation blocks IL-6-induced mTOR activation. In summary, we present a novel STAT3-dependent mechanism of both IL-6-induced activation of mTOR and IL-6-dependent reversion of stress-induced inhibition of mTOR activity.