Abstract
BackgroundInflammatory 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.MethodsWe 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.ResultsInterleukin-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.ConclusionsBoth 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.Graphic abstract
Highlights
Inflammatory reactions are commonly affected by stress responses
The tissue hormone interleukin-6 is an important regulator of the inflammatory reaction
IL-6 induces expression of two suppressor of cytokine signalling 3 (SOCS3) isoforms The feedback inhibitor SOCS3 is rapidly induced in response to IL-6 and other IL-6-type cytokines [7,8,9]
Summary
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. Glucocorticoids that regulate glucose metabolism to increase blood glucose in stress situations increase the hepatic expression of acute-phase proteins [1, 2]. Upon binding of IL-6 to the receptor complex, gp130-associated Janus kinases (JAK) are activated and subsequently phosphorylate tyrosine motifs within the cytoplasmic part of gp130 [4]. These phosphotyrosine motifs are recruitment sites for transcription factors of the signal transducer and activator of transcription (STAT) family. Activation of the inflammatory response must be stringently controlled, negative regulation at the level of signal transduction being of paramount importance
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